Pyrethroid resistance in the dengue vector Aedes aegypti in Southeast Asia: present situation and prospects for management

Pyrethroid resistance in the dengue vector Aedes aegypti in Southeast Asia: present situation and... Human arboviral diseases transmitted by Aedes aegypti such as dengue, Zika, chikungunya and yellow fever remain global public health threats to date. Of these diseases, dengue fever is particularly prevalent in Southeast Asia. Relentless vector control efforts are performed to curtail disease transmissions through which pyrethroid insecticides are broadly used as the first line of defense to control Ae. aegypti, especially in the course of disease outbreaks. Here, we compile the largest contemporary database for susceptibility profiles and underlying mechanisms involved in Ae. aegypti resistant to pyrethroids in Southeast Asia. The extensive use of pyrethroids inevitably elicit different levels of resistance to numerous populations despite the presence of geographical isolation. The most common mechanisms of pyrethroid resistance that have been identified in Ae. aegypti includes mutations in the voltage sensitive sodium channel gene (Vssc gene) and metabolic-mediated insecticide resistance. Aedes aegypti develops resistance to pyrethroids by acquisition of one or several amino acid substitution(s) in this Vssc gene. Enzymes involved in metabolic-mediated detoxification (i.e. monooxygenases, glutathione-S-transferases and esterases) have been reported to be related to pyrethroid resistance but many specific contributory enzymes are not completely studied. An inadequate amount of data from some countries indicates an urgent need for further study to fill the knowledge gaps. Perspectives and future research needs are also discussed. Keywords: Pyrethroids, Insecticide resistance, Knockdown resistance, kdr, Metabolic-mediated resistance Background insecticides and biological control. However, the most Dengue virus (DENV) and other arboviruses such as extensively practiced control for Ae. aegypti, owing to its Zika virus, chikungunya virus and yellow fever virus are high efficacy in regulating the populations with relatively transmitted by Aedes aegypti. This highly adapted spe- rapid action, is the application of chemical insecticides. cies thrives in urban and suburban areas. Effective con- The use of multiple classes of synthetic insecticides has trol of Ae. aegypti is absolutely challenging when this been largely practiced in vector control strategies, with species has deep-rooted and spread extensively in pyrethroid-based formulations massively dominating the disease-endemic regions. With a lack of safe and effect- insecticide market worldwide. ive treatment or vaccine for Ae. aegypti-borne diseases To the authors’ knowledge, there is no study to ad- to date, tactics in suppressing Ae. aegypti continue to be dress the overall prevalence of pyrethroid resistance in the cornerstone in preventing dengue transmission and Ae. aegypti in Southeast Asian countries. Therefore, this outbreak control. systematic review was carried out to determine related An effective vector prevention to transiently remove present situation to deliver datasets which will require in Ae. aegypti involves several strategies such as eliminating vector control management on improving public health potential mosquito breeding sites, applying chemical of human population. * Correspondence: ame_lia1031@hotmail.com; vanlun_low@um.edu.my Burden of pyrethroid resistance in Aedes aegypti Tropical Infectious Diseases Research & Education Centre (TIDREC), Geographical expansion of Aedes aegypti has fostered University of Malaya, 50603 Kuala Lumpur, Malaysia Full list of author information is available at the end of the article the incidence of dengue fevers (DF) to gain an apparent © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 2 of 17 increase worldwide, which put an estimation of almost character in implementing these programmes. However, it half of the world’s population at stake for the disease [1]. should also be stressed that the success of these pro- The most extensively practiced control for Ae. aegypti, grammes can only be accomplished if both parties are owing to its high efficacy in regulating the populations committed to implement procedures in assisting com- with relatively rapid action, is the application of chem- munity participation in Ae. aegypti control. ical insecticides [2]. Pyrethroid insecticides are currently being used extensively to control Ae. aegypti adults Pyrethroid resistance mechanisms worldwide and constitute approximately 17% of the Physiological resistance and behavioral avoidance of Ae. worldwide insecticide market share and 1.4 USD billion aegypti to insecticides are two integral responses as- of global trades [3]. In general, pyrethroids are neuro- cribed to the intensified implementations of chemical- toxins which modify the normal function of insect based control programmes. Physiological resistance im- nerves and cause disruption at the Vssc gene by depolar- plies the survival of mosquito victims under the expos- izing neurons [4, 5], paralyzing and eventually killing the ure to chemical insecticides which would normally lead insect. Deltamethrin, cypermethrin, cyfluthrin, lambda- to complete death, comprising the most well- cyhalothrin, permethrin, alpha-cypermethrin, pyrethrum, documented mechanisms conferring resistance against bifenthrin, d-phenothrin, z-cypermethrin and etofenprox pyrethroid insecticides in Ae. aegypti such as insensitiv- are the major types of pyrethroids used, and that their ity of target site which causes knockdown resistance treatments usually involve either residual or space spray (kdr)[19]; and metabolic detoxification via mixed func- [6]. Narrowing down to Southeast Asia, deltamethrin, per- tion oxidases (P450 mediated monooxygenases), ester- methrin, alpha-cypermethrin, cyfluthrin and lambda- ases and glutathione S-transferases (GSTs) [20]. cyhalothrin are commonly employed in suppressing Ae. Behavioral avoidance is the development of any change aegypti, particularly in Malaysia [7–9], Indonesia [10–12], in the behavior of a mosquito to decrease the exposure Singapore [13–15] and Thailand [16–18]. All the on- of toxic substances or to escape lethal effect of insecti- shelf insecticides available for vector control are cide, but this mechanism is easily overlooked [20]. Other obliged to apply cautiously to delay worldwide evolu- than the aforementioned resistance mechanisms, insecti- tion of mosquito resistance. cide resistance in Ae. aegypti is also mediated by cuticu- Currently, insecticide resistance is one of the most se- lar resistance. Notes on each mechanism are described vere issues facing mosquito control agencies. The loss of as follows. efficacy of pyrethroids may consequently bring high pos- sibility of operational failure of Ae. aegypti-borne dis- eases control and subsequently lead to increased disease Behavioral avoidance transmission. This will cause even larger capital to be In-depth behavioral avoidance studies in Ae. aegypti invested into mosquito control programmes by the gov- are scarce across Southeast Asia until now. A change ernment in return, for examples, the development of in mosquitoes’ feeding or resting behavior to new insecticides in terms of labors and costs, which may minimize exposure to insecticides, this mechanism is cause direct socio-economic impact to a country. Other generally categorized into direct contact excitation than the commonly-reported adverse impacts on public and non-contact spatial repellency [20]. Direct contact health and environment, reports particularly on the eco- excitation (irritancy) is a phenomenon when mosqui- nomic cost of pyrethroid resistance in Ae. aegypti in toes escape from insecticide-exposed environment Southeast Asia have not been presented. This is in large upon physical contact, while non-contact spatial re- part due to the progression of operating and resource pellency is when mosquitoes leaving the toxic area costs throughout the vector control programme since even before getting contact with a treated surface. Re- the first occurrence of control problems until complete lated behavioral avoidance studies of Ae. aegypti ex- control failures have not been described. To expedite the posed to a range of pyrethroids have been inspected progress and execution of scientifically-sound policies of in Thailand, projected that average to strong irritancy insecticide use, economic costs in Southeast Asian con- have demonstrated in all tested populations when text are vital to be studied. compared to repellency [21–24]. Despite the import- A need of new paradigm or choice to control Ae. aegypti ance of behavioral responses of mosquitoes to insecti- is undeniably urgent, provided that the current vector con- cides contribute to the efficacy of chemicals, the trol strategies in Southeast Asia resulted in the discovery of relative complications of the assay designs, for in- insecticide-resistant mosquito populations. The ultimate stance, problems in differentiating between contact goal of a vector control programme should focus on the es- excitation and non-contact spatial repellency re- tablishment of an efficient government-community sponses exerted in mosquitoes, lacking ideal statistical partnerships that the community plays a fundamental methods in analyzing data, and difficulties in Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 3 of 17 introducing and removing test specimens, cause a detected in Southeast Asia; for examples, S989P, dearth of information in this mechanism. I1011M/V, V1016G/I and F1534C based on the mutation positions of house fly sodium channel [10, 37–41]. It is Cuticular resistance no surprise that more sodium channel mutations in re- Cuticle thickening is implicated in insecticide resistance sistant insects have been discovered taking the advantage by reducing the uptake of the insecticide that reaches of the convenience of molecular approach. Beside the the target site in response to the modification of chem- identification of single point mutations, novel co- ical composition of the cuticle. In mosquitoes, cuticular occurrence of mutations was also detected. As firstly resistance is often pointed out but related studies are in- reviewed by Brengues et al. [37], V1016G was closely re- sufficient. A recent study revealed that this mechanism lated to S989P in Southeast Asian countries such as may play a major role in the development of resistance Indonesia, Myanmar, Thailand and Malaysia [9, 10, 39, 42], where it normally happens simultaneously with other and this common phenomenon was believed to confer mechanism(s) [25], causing resistance to single or mul- higher resistance. Co-occurrence of triple mutations tiple insecticides [26]. It has been reviewed elsewhere V1016G, S989P and F1534C would result in even higher that cuticle thickening is associated with metabolic de- resistance to pyrethroids, as seen in Ae. aegypti populations toxification whereby thicker cuticle causes gradual in- from Myanmar [39]. The detection of these specific muta- secticide absorption rate that will increase the tions, such as V1016G, S989P and F1534C, were affirmed effectiveness of metabolic detoxification in Anopheles to confer sodium channel resistance to pyrethroids and funestus [27]. Moreover, it is crucial to take note that in- other associated mutations which are still yet to be sects with cuticular resistance will display resistance inspected. It is very likely for the emergence of new kdr level of not more than 3-fold in comparison to suscep- mutations when pyrethroids remained to be the primary tible insects, but the co-occurrence of other resistance insecticide-based interventions in the control of Ae. aegypti. mechanism will lead to a surge in insecticide resistance Hence, these detections act as a crucial role in resistance level markedly [28]. This is demonstrated by Anopheles management of Ae. aegypti by observing the occurrence of gambiae in Benin [29] through which overexpression of pyrethroid resistance. cuticular genes and P450 genes gave rise to a relatively It is remarkable that despite two distinct substitutions high resistance level. Cuticular resistance to pyrethroids occur at the same amino acid position, V1016G and is also characterized in Ae. aegypti [30] but there is a V1016I display different geographical variations with dis- lack of similar report documented in Southeast Asia. similar response of Ae. aegypti sodium channel to pyre- The fact that this least-understood mechanism may play throids. V1016G has been detected in Southeast Asia substantial role in resistance urges for immediate atten- [37, 39, 40, 43, 44] while V1016I has been found in tion in investigating, particularly in pyrethroid-resistant North and South America [45–47]. In recent times, the Ae. aegypti. V1016I mutation was detected in Vietnam [41] and V1016I along with F1534C was detected in Ghana that Knockdown resistance (kdr) there may be presence of migration event [48]. The de- Target site resistance in mosquitoes is related to either tection of these point mutations in Ae. aegypti strains in single or multiple mutations in target genes; for ex- continents they have never existed before requires fur- ample, the Vssc gene which leads to kdr, mutations in ther validation to confirm if the resistance is caused by the acetylcholinesterase (Ace-1) gene and GABA recep- migration or de novo (new) mutations. The evolution tors [31, 32]. The most well-studied target site resistance and distribution of pyrethroid resistance in Ae. aegypti for Ae. aegypti is kdr because it confers resistance populations is relevant when their eggs can endure des- against pyrethroids. The Vssc gene comprises four hom- iccation for an extended period that permit them to put ologous domains and each of them contains six hydro- human travel to good use. phobic subunits (segments 1–6). In the past few decades, numerous mutations in the Vssc gene have Metabolic-mediated insecticide resistance been documented to be linked to kdr in many insect dis- Metabolic resistance in Ae. aegypti involves alterations ease vectors. The single point L1014F mutation in the in a series of the expression of a complex group of en- domain II segment 6 (IIS6) was the foremost mutation zymes, causing a rise in the detoxification process of in- associated with pyrethroid resistance identified. There- secticides. This resistance mechanism facilitates after, different substitutions of C, F, H, S or W at this increased biodegradation of insecticides, with the help of position have been reported in a few mosquito species in enzymes such as GSTs, esterases and cytochrome P450 the genera of Anopheles and Culex mosquitoes [33–36]. monooxygenases (P450 genes). A total of 160 P450 In Ae. aegypti mosquitoes, L1014 has yet to be identi- genes, 49 GSTs and 26 esterases have been revealed in fied but several different kdr mutations have been an international genome project of Ae. aegypti [49]. Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 4 of 17 Among these, cytochrome P450 genes are the enzyme of the enzyme family are still largely unverified up to family highly responsible for the development of pyreth- now especially in Southeast Asia. roid resistance in Ae. aegypti. Therefore, cytochrome It is indisputably important to investigate metabolic- P450 genes are of interest to study since they are capable mediated insecticide resistance of Ae. aegypti to pyre- in metabolizing xenobiotics such as drugs, plant toxins throids since co-existence of more than one mechanism is and insecticides. One of the most noteworthy character- likely to occur, especially the largest endemic sites of DF istics of P450 genes linked to enhanced metabolic de- Southeast Asia. In addition, efforts should be put in to the toxification of insecticides is the detection of a development of new insecticides, taking these enzymes re- significant rise in P450 proteins and P450 activity due to lated to insecticide resistance into consideration in the the overexpression of insecticide-resistant insects P450 span of design procedure. genes, which is closely associated with the development of insecticide resistance [50, 51]. However, identification Present situation of pyrethroid susceptibility in of enzymes associated with insecticide resistance is diffi- Aedes aegypti in Southeast Asia cult because of the presence of diverse group of P450 Published literature with regards to the insecticide resist- genes and high structural similarity in isoforms that ance profiles of Ae. aegypti against pyrethroids in most of makes identifying isoform related to resistance to be the Southeast Asian countries are detailed as follows. In- challenging. While molecular approaches in detecting formation were extracted from all publications document- Vssc gene mutations in pyrethroid-resistant Ae. aegypti ing mortality, lethal concentration (LC ) and knockdown are broadly documented, they are rare for P450 genes. time (KT ) from bioassays of Ae. aegypti mosquito popu- CYP9 family has been involved in pyrethroid resistance lations using merely pyrethroids. Since our main emphasis in the dengue vector Ae. aegypti [52]. CYP9J22 and was chiefly placed on studies assaying pyrethroids against CYP9M9 were the two P450 genes found with the high- Ae. aegypti, other classes of insecticides tested and species est transcript level of the resistant populations [52]. On other than Ae. aegypti found in the same publication were a global scale, the most frequently found P450 genes are excluded and not reviewed in this study. Kdr assays used CYP9M6, CYP6BB2, CYP9J26 and CYP9J28, which are to observe the effect of control tactics on pyrethroid re- commonly detected to be overexpressed in resistant sistance were also studied. Distribution of different kdr strains in many studies, projecting their capability in me- mutations in Ae. aegypti in Southeast Asia are summa- tabolizing permethrin [25, 53, 54]. rized in Table 1. Approaches employed to detect insecti- Esterase hydrolysis of pyrethroids resulting in the de- cide resistance when it first presents may allow timely toxification process has assumed to involve in metabolic associated management actions. Since there is a deficiency resistance in some cases. This mechanism encompasses of studies on the metabolic resistance in some of the a series of reaction, such as gene amplification, upregula- Southeast Asian countries, genes identified as overex- tion, and/or coding sequence mutations. However, pub- pressed in resistant populations are reported only in coun- lished data on which exact esterases in contributing to tries with related publications. Publications from all years the presence of pyrethroid-resistant Ae. aegypti popula- were retrieved, considered and incorporated into the re- tions in Southeast Asia continues to be scarce. Elevated view. Knowledge gaps which required attention are also levels of GSTs are also commonly associated with in- identified in this review. secticide resistance. Most of the GSTs are made of a super family structure of cytosolic-dimeric enzymes that Cambodia are grouped into a total of six classes, namely Delta, Ep- Although dengue is a major health concern in Cambodia silon, Omega, Sigma, Theta and Zeta [55]. The two lar- [57], there are merely two known studies evaluating in- gest classes of GSTs for insects are Delta and Epsilon, secticide resistance status of Ae. aegypti in the country. provided that Epsilon class is often involved with resist- The first related study was carried out using temephos ance [56]. In Ae. aegypti, there are basically a cluster of (an organophosphate) at Phnom Penh and Kampong eight sequentially arranged genes that mapped genetic- Cham in accordance with WHO standard bioassays [58]. ally to chromosome 2, supercontig 1.291 in the Epsilon Mosquito populations from Phnom Penh revealed teme- GST class [56]. Recently, microarray studies have discov- phos resistance whereas the latter populations were sus- ered some additional members of this gene cluster with ceptible [58]. It is believed that temephos resistance in elevated levels in Ae. aegypti populations resistant to in- Phnom Penh populations led to another more compre- secticides [52]. However, their roles in metabolizing in- hensive study encompassing Phnom Penh, Siem Reap, secticides like pyrethroids are yet to be determined. Kampong Cham and Battambang using both temephos Although esterases and GSTs are usually found overex- and pyrethroids (permethrin and deltamethrin). Resist- pressed in pyrethroid-resistant Ae. aegypti, the causal of ance to permethrin and deltamethrin were reported in specific enzymes to the resistant populations from each Ae. aegypti populations from all the aforementioned Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 5 of 17 Table 1 Distribution of different kdr mutations in unreported point mutations of the kdr gene. This helps Ae. aegypti in Southeast Asia to understand the nature of pyrethroid resistant in Ae. Country Mutation Reference aegypti in this country, given that dengue is endemic year-round in Cambodia. Biochemical mechanisms of Cambodia F1534C [60, 61] Ae. aegypti to pyrethroid resistance have not been V1016G [61] reported. Indonesia V1016G [10, 37, 44, 61, 63, 66] F1534C [10, 44, 61, 63, 66] Indonesia S989P [10, 44, 63] After a first occurrence in 1968, countless outbreaks of V1016G/S989P [10, 44, 63] DF and dengue haemorrhagic fever (DHF) cases trans- mitted by the primary vector Ae. aegypti mosquitoes Laos V1016G [43] have dramatically increased in recent years. The latest F1534C [43] statistic showed 71,668 DF human cases in 2015 [62], Malaysia V1016G [9] covering all 34 provinces of the country. In Indonesia, F1534C [9] pyrethroids have been broadly used since the 1980s Myanmar V1016G [39, 61] against Ae. aegypti but there has been a dearth of know- S989P [39] ledge on published information. Earlier, some pioneer works reported that Ae. aegypti populations from West F1534C [39, 61] Java (Ciamis, Purwakarta and Bogor) and Bandung were V1016G/S989P [39] resistant to permethrin, lambda-cyhalothrin, cyperme- V1016G/F1534C [39] thrin and d-allethrin [11, 37]. Despite high LT values V1016G/F1534C/S989P [39] being recorded [11], their resistant status regrettably Philippines na should not be concluded. The standard susceptible la- Singapore F1534C [25, 93] boratory strain used as a control in the study appeared to be resistant, led to an uncertainty of the resistant sta- V1016G [25, 40, 93] tus. More recently, published data showed the presence Thailand I1011V [40] of pyrethroid resistance in Ae. aegypti even after ap- F1534C [60, 61, 108] proximately 10 years of the pioneer studies [10, 44, 63]. S989P/V1016G [42, 112] Their susceptibility profiles suggested similar trends of V1016G [37, 40, 61] resistance to pyrethroids [10, 44, 63], signifying compar- V1016G/F1534C/S989P [109] able patterns of insecticide usage in these sampling sites. Over the years, biochemical studies have acknowl- Timor-Leste na edged the role of detoxifying enzymes in the develop- Vietnam V1016I [41] ment of pyrethroid resistance in Ae. aegypti. The first I1011V [126] small-scale test in determining the resistance mecha- F1534C [126] nisms involved in pyrethroid-resistant Ae. aegypti was V1016G [126] accomplished in 2007, comprising strains from Bandung, Abbreviation: na, not available Palembang and Surabaya [12]. Adult Ae. aegypti from Bandung demonstrated the highest resistance level to study sites [59]. Therefore, a nationwide assessment is both permethrin and deltamethrin, corresponding to the recommended to examine pyrethroid resistance in Ae. high levels of activity of enzymes tested, i.e. oxidases, es- aegypti since Cambodia is a country bordering the terase A and esterase B, that play roles in the develop- dengue-endemic countries Thailand, Laos and Vietnam, ment of resistance to pyrethroids. In contrast, another so as to develop effective vector control methods to halt study [64] showed that larvae from most sampling sites the spread of DF. in Cimahi were still susceptible to pyrethroids although In Cambodia, the point mutations of the kdr gene re- Bandung situates in absolutely close proximity to lated with pyrethroid resistance of Ae. aegypti were ana- Cimahi. Adult susceptibility profile may greatly correlate lyzed alongside with samples from other Southeast Asia with larval susceptibility profile in some cases [7, 65]. countries in two international studies. The F1534C mu- However, it should be remembered that there is a differ- tation was detected in the first study [60] whereas ence between resistance score in larvae and adults be- C1534 mutant alleles (with VV/CC patterns) were de- cause they may develop dissimilar resistant mechanisms tected in the second study [61]. Further detection is through different mechanism pathways from larval to highly sought after due to a deprived of nationwide stud- adult stages [14]. Thus, adult bioassay is still required to ies that may possibly lead to the discovery of other verify the resistance status. Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 6 of 17 Other than the responsibility of detoxifying enzymes in control after the official ban of DDT in 2010 [70], the insecticide resistance mechanisms, mutations in the more comprehensive studies are needed in Laos, as Vssc gene should also be highlighted because they may act this knowledge is fundamental in managing vector as markers for resistance monitoring. In Indonesia, kdr control programmes. profiling of Ae. aegypti had recorded three point mutations related to pyrethroid resistance, namely the S989P, V1016G Malaysia and F1534C mutations [10, 37, 44, 63, 66]. The discovery DF or DHF has been a critical public health concern in of the V1016G mutation was first reported by Brengues et Malaysia at all times since the first outbreak in 1973. Re- al. [37] in the Semarang strain. Later, some findings were gardless of extensive fogging operations with malathion in agreement that all three mutations in Vssc gene were de- in Malaysia as early as the 1970s, and followed by the re- tected in Ae. aegypti populations from Yogyakarta, Central placement of pyrethroids like permethrin and deltameth- Java Province, Denpasar and Jakarta [10, 44, 63, 66]. The rin in early 1998 until today [71], dengue remains V1016G mutation was most frequently detected in high number one infectious disease with a total of 101,357 frequencies, remarkably associated with permethrin and cases reported in the country [72]. Numerous surveil- deltamethrin resistance in Ae. aegypti. Previous reports dis- lance activities have been conducted to investigate in- covered relatively low frequency of the F1534C mutation, secticide susceptibility status of Ae. aegypti. The first which did not demonstrate significant contribution to the study examining on the pyrethroid resistance level of Ae. resistance development of pyrethroids in Ae. aegypti aegypti in Malaysia was accomplished in 2001, using [10, 44, 63, 66]. As for the S989P point mutation, it field strains from Kuala Lumpur, Selangor, Negeri Sem- generally co-occurred with the V1016G mutation, bilan, Johor, Kelantan and Pahang. The urban strain of showing association on pyrethroid resistance develop- Ae. aegypti from Kuala Lumpur showed the highest re- ment in Ae. aegypti. Furthermore, the frequency of the sistance to permethrin, validating the high levels of es- V1016G mutation occurred in Ae. aegypti in the Cen- terase compared to the laboratory strain [73]. This result tral Java has increased two-fold in just a decade, com- was in agreement with the findings performed after al- pared to a report generated earlier [37]. These most a decade. Permethrin resistance persisted in field preliminary detections of insecticide resistance will fun- strains of Ae. aegypti collected from dengue-endemic damentally aid in initiating appropriate control mea- areas of Kuala Lumpur [7]. Both larval and adult bioas- sures in delaying development of mosquito resistance, says of the field strains confirmed the development of for instance rotation of insecticide or addition of cata- tolerance towards permethrin with several folds higher lyst to enhance the efficacy of insecticides in suppress- than the laboratory strain [7], indicating high reliability ing Ae. aegypti in Indonesia. on chemical insecticides to control Ae. aegypti in an un- precedented scale at the dengue hotspots. Piperonyl but- Laos oxide (PBO) was also reported to be effective in Compared to the neighboring countries, there is a enhancing the effectiveness of permethrin through scarcity of study on pyrethroid resistance in Ae. which strong correlations were confirmed between LC aegypti in Laos. The first DF outbreak was recorded or LT values and oxidase levels for all strains [7], im- in 1998 in Khammouane Province [67]. Although plying the involvement of oxidase activity in causing per- Ae. aegypti has been stated to be the main vector methrin resistance in this mosquito species. of numerous mosquito-related diseases in Laos Another similar study performed at dengue-prone sites [67, 68], with 22,772 cases of dengue reported dur- of Selangor documented resistance and incipient resist- ing 2010 [69], there is only a single report investi- ance of Ae. aegypti to permethrin (mortality ≤ 80%) and gating pyrethroid resistance status of Ae. aegypti in cyfluthrin (mortality 45–97.8%), respectively [8]. Al- the country thus far. Samples were collected from though cyfluthrin was not used by the municipal in vec- five provinces and populations involved in the study tor control programme, fluctuated resistance was identified high level of resistance against permeth- detected and this may be attributed to the role of kdr. rin, which contrast with deltamethrin that exhibited Screening of kdr is yet to be performed in Selangor but high susceptibility in Ae. aegypti [43]. Higher quan- it has already accomplished and confirmed on the pres- tities of P450 genes were detected in field compared ence of kdr in Kuala Lumpur [9], which is very close to to reference strains but no particular CYP was Selangor. DDT resistance was also detected over the mentioned. The frequencies of kdr mutations were course of the study [8], further supporting the role of low for the V1016G mutation (< 0.36) but relatively kdr in both pyrethroid and DDT resistance due to the higher for the F1534C mutation (> 0.6 for majority shared Vssc target site. GST activity exerted on DDT re- of places). With a total of 18 provinces available in sistance has not been discovered in Malaysian mosqui- Laos and a reliance upon pyrethroids in Ae. aegypti toes including Ae. aegypti [71, 74]. The widespread of Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 7 of 17 insecticide resistance pays full responsibility to failures w/w of d-trans allethrin were proven to show higher in vector control programme. Aedes aegypti populations repellent efficacies and mortality [82]. However, this re- from mainland Penang were also highly resistant to sult requires further verification on field strains in nat- lambda-cyhalothrin [75]. These outcomes were sup- ural settings. In the past decades, efficacy studies were ported by the fact that pyrethroids have been broadly performed on the laboratory strains of Ae. aegypti. Until sprayed in the study areas for more than 10 years. Of recently, insecticidal activities of Malaysian commercial several studies conducted in the country, insecticide sus- coils have been assessed on field strains of Ae. aegypti in ceptibility status of permethrin was often tested against a nationwide-scale. Aedes aegypti from a total of 11 Ae. aegypti in Malaysia because this insecticide is one of states were discovered to be resistant to mosquito coils the main adulticides used in Malaysia [76]. Moreover, containing active ingredients of d-allethrin, d-trans alle- the development of permethrin resistance at a higher thrin, metofluthrin and prallethrin, according to the re- rate than malathion and temephos [77] might be closely sistance index recommended by the WHO [83]. Since associated with gene activation due to the exposure to there is a wide array of insecticides used intensively in insecticidal pressure. the country to curtail disease transmission, either opera- More recently, despite discrepancies of insecticide sus- tions conducted by the Ministry of Health, private com- ceptible status found in the field strains of Ae. aegypti panies or even at household level [84], it is utmost from Kuala Lumpur, Penang, Johor Bharu and Kota important to assess regularly on the efficacies of insecti- Bharu tested against permethrin and deltamethrin, the cides used to guarantee effective vector control mosquito strains from Kuala Lumpur remained to ex- programme. hibit the highest resistance levels [9]. Synergist assays with PBO showed that metabolic resistance mechanisms Myanmar played key role in certain strains. This particular study is The first documented outbreak of DHF was in 1969 and the first report in Malaysia in characterizing the kdr re- then the outbreaks gradually increased to 12 out of 14 sistance in Malaysian populations of Ae. aegypti. The states in Myanmar [85]. This disease was documented V1016G and the F1534C mutations were detected, with with a high of 83,381 cases, causing 3243 deaths be- the F1534C mutation closely associated with pyrethroid tween 1970–1991 [85]. No sign of decrement in DHF resistance whereas the V1016G mutation co-occurred to incidence with 5621 cases in 2005 to an approximate contribute to the additive effect of pyrethroid resistance two-fold of 11,049 cases in 2006 [86], despite persistent in Malaysia [9]. A microarray-based genome-wide tran- control efforts made by the Myanmar government since scriptional analysis discovered that metabolic resistance 1968 [85]. Although the significance of the disease re- of pyrethroid resistance in Ae. aegypti populations is quires immediate attention, there is only a single report predominantly caused by overexpressed of the cyto- on the ecological study of Ae. aegypti focusing on the chrome P450 genes (CYP9J27, CYP6CB1, CYP9J26 and southern part of Myanmar [86]. There is still an unavail- CYP9M4)[32]. However, more characterization work on ability on the bioassay studies of the status of pyrethroid the cytochrome P450 family must be carried out to resistance in Ae. aegypti in the country. understand the precise roles of these genes in contribut- There is an absence of study to date, regarding the ing pyrethroid resistance in Ae. aegypti. biochemical mechanisms of Ae. aegypti to pyrethroid re- As far as we know, Malaysia is one of the two coun- sistance. In 2014, a project was initiated to evaluate the tries in Southeast Asia tested on the efficacies of the types and frequencies of point mutations of the kdr gene commercial mosquito coils against Ae. aegypti. The mos- related with pyrethroid resistance of Ae. aegypti.Itwas quito coil is one of the most extensively-used anti- revealed that V1016G and S989P mutations were exten- mosquito household spatial repellents in Malaysia, ac- sively scattered in Yangon city with high frequencies of counting for the low costs and easy availability on-shelf 84.4% and 78.8%, respectively [39]. Another widely scat- countrywide [78–81]. In 1996, the first study assayed on tered point mutation identified with relatively low allelic the efficacies of mosquito coils containing active ingre- frequency of 21.2% was F1534C [39]. Other than three dients like d-allethrin (0.2% w/w) and d-trans allethrin single point mutations were detected in Yangon city, (0.1% w/w) against laboratory Ae. aegypti were accom- three patterns of co-occurrence of point mutations were plished, revealing adequate knockdown effects but with also identified with widely distributed homozygous minimal mortalities for both coils [78]. After almost a V1016G/S989P mutations (65.7%), as well as a small num- decade, a similar study was conducted with the use of ber of homozygous V1016G/F1534C mutations (2.9%) d-allethrin (0.2% and 0.3% w/w) and d-trans allethrin (0. and homozygous V1016G/F1534C/S989P (0.98%) [39]. It 1% and 0.2% w/w) on laboratory strain of Ae. aegypti should be noted that the observed types and frequencies [82]. Dosage increment of the active ingredients in mos- of resistance alleles may be very well representing the Yan- quito coils, which are 0.3% w/w of d-allethrin and 0.2% gon city, as samples were collected from seven townships. Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 8 of 17 However, it may not be a decent approximation of types ever since they were first introduced in Singapore. The and genotype frequencies of the country because the size use of synergists (piperonyl butoxide, S,S,S,-tributyl of Yangon city (598.75 km ) is relatively small compared phosphorotrithioate, and triphenyl phosphate) was also to Myanmar (676,578 km ). Therefore, sampling is needed deemed to be insignificant to the insecticides used in throughout the country to ensure the surveillance of these studies to increase toxicity, signifying negligible resistance genes in wild Ae. aegypti populations are roles of metabolic-based resistance when further bio- comprehended. chemical investigation discovered that detoxifying en- zymes such as monooxygenases, esterases, and GSTs Philippines failed to contribute to pyrethroid resistance [14, 15]. The There appears to be an agreement in literature that Ae. ineffectiveness of synergists proposes that molecular aegypti was introduced into the Philippines approaching work is recommended to further investigate the mecha- the end of 19th century and followed by the proliferation nisms contribute to the high pyrethroid resistance exhib- of this dengue vector [87]. However, there are only two ited in local Ae. aegypti. known studies evaluating the insecticide resistance of Other than fogging, space spraying, chemical treat- Ae. aegypti to pyrethroids in the Philippines. In the first ment and source reduction as dengue vector control study, Ae. aegypti from Luzon Island, Manila was con- methods, deltamethrin-treated net is an alternative. firmed to be susceptible to dieldrin even after eight years However, its efficacy was proven to be unsatisfactory of insecticide application in the country since 1959 [88]. against field Ae. aegypti in a recent study [93]. Three Currently, the latest susceptibility test of Ae. aegypti with molecular investigations have evaluated the roles of indi- the use of pyrethroid was completed in 1997 in Cebu vidual and multiple Vssc gene mutations in contributing city. It was proven that treatment of curtains with per- to the developed pyrethroid resistance in Singaporean methrin was an effective vector control measure [89]. Ae. aegypti: F1534C, S989P+V1016G and F1534C These preliminary studies facilitated in verifying the de- +V1016G [25, 93, 94]. However, in-depth study showed velopment of resistant strains in the country but the in- that G1016 alleles independently pay more responsibility formation may not be up to date, and related studies are to Vssc gene insensitivity than C1534 alleles independ- recommended in the future because DF is endemic in ently [25, 94]. To the best of our knowledge, S989P neighboring countries like Malaysia. Susceptibility tests +V1016G+F1534C triple mutations in Vssc gene exhib- of different pyrethroids and related resistance mecha- ited in the local Ae. aegypti were first reported in nisms should be attempted on different field populations Singapore. They exerted the largest pressure in channel of Ae. aegypti in the country to confirm insecticide sus- sensitivity to permethrin and deltamathrin by 1100-fold ceptibility status and guarantee the representativeness of and 90-fold [94], implying the likelihood of reduced effi- the information generated since those insecticides have cacy to pyrethroid insecticides. There is also a need of been put to use for several decades. an immediate attention to monitor the occurrence of triple mutations in Vssc gene of field Ae. aegypti popula- Singapore tions worldwide, so that the challenge of mosquito vec- It is clear that Ae. aegypti mosquitoes are the primary tor control will not further exacerbated. The significance vectors of DF in Singapore, with the first dengue case re- of P450-mediated resistance is mirrored by the highly- ports in the 1960s [90]. In the 1970s, pyrethroids were resistant Ae. aegypti Singapore (SP) strain, showing first introduced to the country to deprive the popula- 1,650-fold of resistant to permethrin and PBO has re- tions but permethrin resistance was identified in field duced the resistance by 48-fold [25]. P450 genes Ae. aegypti later [91]. Subsequently, an assessment in (CYP4C50, 6BB2, 6F2, 6F3, 6Z7, 6Z8, 9M4, 9M5 and 1999 revealed a 12.9-fold of RR of field Ae. aegypti 9M6) were also discovered to be overexpressed in adult against permethrin [13]. Resistance of Ae. aegypti to females and males [25]. Precise and reliable molecular cypermethrin was also reported in a study between diagnosis approach to identify metabolic enzymes con- 2004–2007 [92]. More recently, the detection of resist- ferring pyrethroid resistance in Ae. aegypti populations ance of Ae. aegypti to pyrethroids were further verified should be emphasized to elucidate the contribution de- by two comprehensive nationwide insecticide resistance gree of P450 genes to field-resistant strains from distinct studies on larvae tested with permethrin and etofenprox, areas. as well as adults with cypermethrin, deltamethrin and etofenprox [14, 15]. Despite the a few decades of gap be- Thailand tween these studies, high resistance to pyrethroids Thailand is the country with the most studies evaluating remained to persist in the Singaporean Ae. aegypti popu- on the insecticide resistance of pyrethroids to Aedes lations and they continued to thrive, portraying the aegypti in Southeast Asia, reflecting a substantial geo- widespread or probably inappropriate use of pyrethroids graphical bias as this species is widespread in many Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 9 of 17 countries in this sub-region. Thailand first experienced irrefutably important when mosquito coils are the top outbreaks of dengue hemorrhagic fever in 1958 and the choice of household insecticide formulations worldwide disease has since then distributed nationwide [95]. To other than aerosols, vaporizing mats and liquid vaporizers. date, DF or DHF remain a severe health threat in The first report was completed in 2008 in Thailand, show- Thailand regardless of unrelenting vigilance in vector ing a phenomenon of tolerance of Ae. aegypti to dl, d- control programmes. Reliance has been on the carba- T80-allethrin, d, d-T-prallethrin and methoxymethyl-tet- mate, organochlorine and organophosphate insecticides rafluorobenzyl tetramethyl-cyclopropanecarboxylate (K- since 1950 [17] and the use of synthetic pyrethroids then 3050) under semi-field condition [103]. A similar study dominated the market since 1992. Pyrethroid-based for- was conducted with a total of four field strains of Ae. mulations with 12 distinct active ingredients are com- aegypti tested against the same active ingredients, employ- mercially available to all household levels countrywide to ing 25 m semi-field test system, topical application test control mosquitoes in response to their low price, quick and field efficacy test [104]. Most of the strains were re- knockdown effect and are relatively safe for human con- corded to be tolerant to the mosquito coils tested but pyr- tact because of low mammalian toxicity [17]. Years of ethroid resistance may have already developed since routine contact with these insecticides have induced noticeably large gaps were observed between the time- high levels of resistance in Ae. aegypti. frame of sample collection and the course of the study, To understand the insecticide susceptibility profile of with up to 31 years gap. It is recommended that, when Thai Ae. aegypti to pyrethroids, there have been several possible, mosquito test populations should be acquired published pioneering works available, but specific geo- with shorter gap to prevent bias in the outcomes. The lat- graphical restrictions were observed whereby they were est related study was accomplished in 2009 using 25 m conducted in small confined areas during previous de- semi-field test and topical application test, demonstrating cades. Increasing tolerance or resistance to different extremely low susceptibility to dl, d-T80-allethrin in some types of pyrethroids, namely deltamethrin, permethrin, field strains [105] and that they may have already devel- dieldrin, bioallethrin, bioresmethrin or alphacyperme- oped resistance now. All three studies yielded similar out- thrin, has been reported in larval and adult Ae. aegypti comes with low allethrin susceptibility, but it should be in Thailand [16–18, 96–101]. The absence of large scale noted that direct comparison of results should be avoided evidence-based understanding of the knowledge between due to different testing approaches used. Standardization the susceptibility profile and insecticides used may of method is needed to avoid significant data deviation largely hinder the effect of dengue control efforts. A from a study to another. The knockdown time may vary comprehensive study evaluating the insecticide suscepti- in regard to types of method employed, that according to bility level will aid in better efficiency in programme- Chadwick [106], results carried out in cylinders, small planning to target the disease vector. More recently pub- chambers and large rooms are distinct. Moreover, associ- lished data on pyrethroid resistance in Thai Ae. aegypti ated assessments on the efficacy of mosquito coil to Thai addressed the issue that all 32 strains of Ae. aegypti were Ae. aegypti are also needed. discovered to be resistant to permethrin, ranging A simple colorimetric assay based on Heated Oligo- between 4.0–56.4% [102]. The frequency of susceptibility nucleotide Ligation Assay (HOLA) kdr assay from past to deltamethrin in this species showed more than 98% of studies was developed to detect substitutions within do- mortality to deltamethrin in the majority of the popula- main II, subunit 6. i.e. Met1011, Val1011, Ile1016, and tions, with incipient resistance detected in minor popu- Gly1016 [40]. The V1016G mutation was evidently de- lations. Conversely, all 32 strains of Ae. aegypti were tected in high allele frequency of 0.23 throughout entirely susceptible to lambda-cyhalothrin with 100% Thailand in pyrethroid-resistant Ae. aegypti, and that the mortality. Significantly high levels of permethrin resist- I1011V mutation to be the minority with an allele fre- ance were documented by [18] (5% mortality) and [96] quency of 0.14 [40]. Despite only a thermal cycler being (2–9% mortality) which contrast with this particular involved in this assay, extra reagents are needed which study. This may attribute to the differences in sampling contributes to the increment of cost. An allele-specific sites and the alterations in levels of exposure to polymerase chain reaction (AS-PCR) assay was then de- permethrin. veloped to detect the V1016G mutation which was Personal protection tools, for instance mosquito coils, shown to be reliable [107]. Homozygous 1016G mosqui- are extensively used in Thailand but these products have toes were found to be common in Thailand and showed never been thoroughly studied. Although literature pre- higher survival rates than either heterozygous or wild- sents on the efficacies of commercially available mos- type (1016V) mosquitoes upon deltamethrin exposure, quito coils, up to now, information about detailed indicating this particular mutation confidently related to assessment on these coils to field populations of Ae. deltamethrin resistance. Subsequently, the F1534C mu- aegypti remains to be sparse. These studies are tation was discovered as a novel amino acid mutation in Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 10 of 17 2010 in permethrin-resistant Ae. aegypti, and was re- deltamethrin exposure earn further attentions. This ported to play a significant role in contributing permeth- overlaps the study of Somwang et al. [111], which de- rin resistance in multiple field strains [108]. The wide scribed oxidative enzyme systems also involve in pyreth- distribution of this mutation led to the development of roid resistance in Ae. aegypti in Thailand. Another study high-throughput molecular tools, namely TaqMan single showed that biochemical assays are very much required nucleotide polymorphism (SNP) genotyping and an AS- when a difference of low kdr resistant allele frequency of PCR assay, which proved to be consistent in detecting S989P and V1016G with high level of permethrin resist- the F1534C resistance mutation in the permethrin- ance was reported in field strains of Ae. aegypti, which resistance Ae. aegypti populations [108]. Recently, a this implies detoxification enzymes show the possibility multiplex polymerase chain reaction (PCR) was devel- to be involved in insecticide resistance mechanisms oped to detect both V1016G and F1534C kdr mutations [112]. in Ae. aegypti through a single-reaction protocol [61]. Biochemical assays used to detect enzymes metaboliz- This method was evidenced to depict high sensitivity ing insecticides have been available for over three de- and specificity in detecting the aforesaid kdr mutations, cades to monitor insecticide resistance of Ae. aegypti in enabling the monitoring of the frequency of mutant various countries. In Thailand, the first related study was alleles across dengue-endemic countries at ease with re- accomplished in 2002 using laboratory bred artificially duced time and cost. selected resistant Ae. aegypti. GST and esterase activities Other than the discovery of singly-occurred mutations, were detected to be only marginally higher relative to the novel co-occurrence of the S989P mutation and the the susceptible strain, signifying that both enzyme V1016G mutation were detected in Thai deltamethrin- groups show no major role in permethrin resistance resistant Ae. aegypti [42]. The 1016G mutation usually [113]. In contrast, the subsequent biochemical assay of coexists with 989P mutation but there is also an absence metabolic enzymes tested with field Ae. aegypti to pyr- of 989P mutation in some Thai populations which were ethroid resistance revealed esterase, monooxygenase and homozygous for 1016G [37]. Since some studies showed GST are closely associated with permethrin resistance that the V1016G mutation has been reported in the ab- whereas deltamethrin resistance is related to esterase sence of the S989P mutation, it is likely to hypothesize and monooxygenase [21]. Later, a number of studies that this point mutation acts as an additive mutation proposed that an elevated level of mixed function oxi- [42]. Furthermore, the V1016G/F1534C/S989P muta- dase was usually in association with pyrethroid resist- tions have been confirmed in Thailand, demonstrating ance [16, 114]. Moreover, considerable escalated levels of an additive effect on deltamethrin sensitivity which gives esterases and GSTs were stated in some field strains of high level of resistance [109]. Recent work has also em- pyrethroid-resistant Ae. aegypti [114]. The latest study phasized that the variations of point mutations exerted demonstrated that the aforementioned enzymes were ei- on pyrethroid-resistant Ae. aegypti revealed different re- ther unrelated or merely contributed partially in pyreth- sponse to insecticides. Thermal fogging spray with delta- roid resistance [115]. In regards to the discrepancies of methrin and PBO synergist killed all resistant genotypic these enzymes as contributory factors to pyrethroid re- mosquitoes in indoors [110]. In contrast, the outdoor sistance in Ae. aegypti, it should be noted that in vitro spray displayed minor impact on the G1016 homozygous experiments may not reflect the in vivo circumstances of mosquitoes, partially killed the G1016/C1534 double insect metabolizing insecticide molecules and thus, field heterozygous mosquitoes and triggered high mortality in studies including numerous variables should be consid- the C1534 homozygous mosquitoes [110]. Further asso- ered in the future. ciated studies should be conducted to understand other polymorphisms complementing the Vssc mutation and Timor-Leste how they are related to the resistance phenotype when Timor-Leste is not excluded from vector-borne diseases selection pressure is extrapolated to act on the survival transmitted by Aedes mosquitoes, due to its generally of pyrethroid-resistant Ae. aegypti. Moreover, further warm and humid climate which is conducive for their verification is also needed to make implications that the growth. Dengue cases were first reported in 2003, aforesaid mutations are linked to deltamethrin resist- followed by an outbreak resulted in 933 cases and 37 ance. Other than the target site insensitivity mechanism deaths in 2005 in Dili, Bobonaro and Baucau [116, 117]. acts upon the pyrethroid resistance in Ae. aegypti, a pre- Although Ae. aegypti was extensively spread in the vious study addressed the absence of the 1016G muta- country [116], there was only single international project tion in deltamethrin resistance mosquito strains and carried out, by Frances et al. [118] who employed bottle revealed the role of mixed function oxidases in confer- bioassay to examine insecticide resistance in Ae. aegypti ring the resistance [16]. Thus, the contributions of meta- and the respective biochemical mechanisms using pyre- bolic mechanisms in these wild-type individuals upon throids (permethrin, resmethrin, lambda-cyhalothrin). Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 11 of 17 These insecticides were in line with the other insecti- pronounced increment of resistance in Ae. aegypti to d- cides used more than a decade ago for vector control allethrin with decrease in the latitude of sampling sites programmes in the country as stated by Whelan & Petitt [125], corresponding to the findings of an earlier study [117]. Since pyrethroid resistance was detected in Ae. [124]. Analysis of point mutations was further investi- aegypti collected from a single site in Dili with elevated gated and the F1534C mutation was verified to be the levels of esterases, there is a need in investigating the ef- chief point mutation that gave rise to high resistance in ficacies and mechanisms contributed to the resistance of the specimens collected from the South, whereas the pyrethroids towards the Ae. aegypti populations in heterozygous V1016G mutation was very low in fre- Timor-Leste. quency [126]. Although low frequencies were detected in the North and the percentage of homozygous F1534C Vietnam remained low (7.4%), unrestrained use of photo-stable DHF was first documented in Hanoi, Vietnam in 1958 pyrethroids that persists in the environment may induce [119], followed by the first and second outbreaks recorded selection pressure for this point mutation, which will re- in 1960 and 1963, respectively, in South Vietnam [120]. sult in more resistance offspring. With 21,000 liters of Vietnam, like all the other Southeast Asian countries, uti- pyrethroids used in dengue control operations in 20 lizes chemical insecticides as the primary tool in ceasing southern provinces in 2007 [127], it is no surprise that spread of the vector of DHF, Ae. aegypti. Although Ae. Ae. aegypti populations from Vietnam have developed aegypti was introduced to the country in 1915 [121]and insecticide resistance. Therefore, the use of PBO as a DHF has been reported to be endemic in Vietnam for synergist was considered to increase the efficacy of detal- decades [122], there are insufficient amount of studies methrin to Ae. aegypti from Nha Trang [41]. The study available in evaluating the efficacies of pyrethroids to Ae. subsequently proved that synergists might play crucial aegypti and their related mechanisms [41, 122–126]. role in Ae. aegypti control programme [41]. Moreover, The first insecticide resistance study of Ae. aegypti was Nha Trang strain housed multiple resistance, the overex- conducted in 1998 and 1999, showing that the mosqui- pressed P450 gene CYP9J32 relative to the susceptible toes were resistant to few pyrethroid insecticides in sev- strain was found capable in metabolizing deltamethrin eral locations of Central Highlands and Nam Bo [122]. effectively, as well as two homozygous kdr mutations Later, a similar but more comprehensive study was com- which were the I1011V (100%) mutation and the V1016I pleted in 2004, encompassing four regions of Vietnam, (67%) mutation. Attention should be paid to the detec- and revealed that Ae. aegypti from numerous locations tion of the V1016I mutation in Vietnam when this point in the Centre and North regions were susceptible to py- mutation was only circumscribed in the continent of rethroids but those from South and Central Highlands America in the past [38, 45, 128]. Thus, consistent mon- were more resistant [124]. This was believed to be re- itoring of insecticide resistance is required. lated to the frequent and prolonged use of pyrethroids in the highlands for the Ae. aegypti control programme Future challenges and perspectives [124]. Apart from the aforementioned factor that may When development of resistance has become a world- influence the susceptibility status of Ae. aegypti to pyre- wide issue, there are alternatives to control Ae. aegypti. throids, mosquitoes from places with high populations Environmental control in Southeast Asia involves source develop higher resistance than those from outskirts; Hu- reduction and the use of mosquito traps or screen net ber et al. [123] showed that Ae. aegypti in cities with covers [129–132]. Standing water and unnecessary con- high populations, like Ho Chi Minh City, developed tainers, in both indoor and outdoor conditions, should higher resistance than those from the outskirts or Long be eliminated to prevent breeding of mosquitoes, specif- An Province. Other than inspecting previously reported ically Ae. aegypti and other container breeders [79]. dengue hotspots, these pioneer studies provided insights Containers that performed functions in daily life should into pyrethroid resistance in Ae. aegypti and reported be screened or properly covered. Source reduction that Ae. aegypti populations in the country had already should also include getting rid of natural habitats that developed resistance to some pyrethroids. collect water, such as bamboo stumps and tree holes to The most extensive nationwide assessment of pyreth- avoid the breeding of Ae. aegypti. roid resistance in Ae. aegypti was completed in 2009, ap- To diversify the choices of vector control, research has proximately a century after this disease vector made its been reinforced in developing pathogenic organisms to way to Vietnam. A total of 527 collection points were in- combat dengue vector. In biological control, natural en- volved from northern to southern Vietnam [125]. A sim- emies are either predators, microbes or parasites [79]. ple bioassay of fourth instar larvae using glass vials was Examples of biological control in Southeast Asia include developed to detect knockdown susceptibility [125]. The the participation of predaceous aquatic insects as natural most notable outcome of this study demonstrated a enemies to suppress mosquito populations by predating Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 12 of 17 on mosquito larvae as food source [57, 133, 134] or the distribution in published reports with more than half use of the entomopathogenic bacteria Bacillus thurin- published from Thailand, Indonesia and Malaysia. Al- giensis var. israelensis to destroy the gut lining of mos- though studies retrieved from the database reflected the quito larvae [130, 135]. Hypothetically, predaceous burden of DF, it is believed that some dengue-endemic animal species should result in reduction of mosquito countries such as Vietnam and Myanmar may have re- populations, but there is limited evidence regarding tan- stricted the accessibility of the database without releas- gible proof of related declining disease burdens. There- ing to the public. This leads to difficulty in deciding on fore, it should be noted that these methods would work suitable insecticides for dengue control and, therefore, a well alongside chemical insecticides but should never be platform with insecticide resistance status of different employed as a sole control tactic during epidemic out- Ae. aegypti populations in a homogenous format would breaks of dengue when immediate elimination of disease critically solve related challenges and ease future vector vectors should be prioritized. control planning. In certain cases, uniformity of proto- Another biological control method involves the release cols was neglected. Examining the broad range in the of Ae. aegypti infected with Wolbachia. These naturally- methodologies utilized to record and analyze resistance occurring bacteria infect a wide range of arthropods and or susceptibility data of various studies is very challen- nematodes but are absent in Ae. aegypti [136]. To de- ging. Thus, only some attempts were made to specify crease dengue transmission, Wolbachia from naturally the level of susceptibility that the standardization of infected organisms are vertically transmitted into Ae. methods in all of the studies would contribute to reliable aegypti. This causes sterility via cytoplasmic incompati- comparison of the outcomes. Method of recording in- bility, resulting in eggs without progeny when an secticide resistance should be consistent, taking LC / uninfected female Ae. aegypti mates with a Wolbachia- LT /KT or other similar set of data for instance, 50 50 infected male [137]. Wolbachia has drawn much atten- though actual values may still have to be provided for tion and field trials are ongoing in several countries such comparison in some circumstances. as Australia [138], Vietnam [139] and Indonesia [140]. In addition, the use of the revised version of World Despite wMel Wolbachia showing positive result in low- Health Organization (WHO) guidelines was not prac- ering the incidence of dengue in human populations in ticed in all the studies. WHO has initially published two northern Australia [138], wMelPop Wolbachia with even different databases on the diagnostic dosages of distinct more significant resistance to DENV infection failed to insecticides [142, 143]; there are still some studies that establish successfully in Australia and Vietnam. Hence, employed the original diagnostic doses to examine the more progressive studies pertaining to the large-scale susceptibility status of Ae. aegypti [8, 13, 18], while some field release of Wolbachia-infected Ae. aegypti are essen- have already opted for the newly revised guideline tial before this approach would show success in dengue [97, 99]. In recent times, WHO has released the latest control programmes throughout dengue-endemic version of test procedures to detect insecticide resistance countries. for both Aedes larvae and adults [144]. All researchers It is irrefutable that chemical insecticides remain the are recommended to adhere to the changes made by primary vector-control intervention, specifically during WHO on the guidelines to evaluate the resistance status an emergency epidemic. When Ae. aegypti exhibited a of field Aedes population. Furthermore, future studies propensity to develop resistance to countless groups of should pinpoint on widening the number of sampling chemical insecticides leading to loss of functions, insect sites on a wide array of active ingredients of the pyreth- growth regulators (IGRs) may likely reduce resistance roid group that are yet to be tested in most cases, developing. The discovery of IGRs is in accordance with including resmethrin, bifenthrin, flumethrin and tralo- the knowledge of their growth, development, function methrin. These may have potential in effective control of and behavior. Thus, the use of IGRs has the likelihood Ae. aegypti or cross-resistance within the active ingredi- to conquer the market of many other insecticides, and ents of the pyrethroid group that may have already oc- Lau et al. [141] reported that this group of insecticides curred whereby the last resort would be abandoning of poses encouraging results to control the field popula- the pyrethroid group of insecticides. The prevalent use tions of Ae. aegypti, specifically cyromazine. of pyrethroid-based mosquito coils calls for further val- Pyrethroid resistance in Southeast Asian Ae. aegypti idation on their efficacies across Southeast Asia. As of should not be overlooked. Many countries rely on the now, little has been reported on the efficacies of these interventions of chemical insecticides to control the mosquito coils to Ae. aegypti populations. mosquito vectors of dengue. In this review of literature, Efforts of understanding the aforementioned mecha- several issues that highlight the need for immediate at- nisms on Ae. aegypti are urgently required, especially in tention are addressed. Undeniably, these studies demon- some dengue-endemic countries with unavailability of strated a strong tendency of lopsided geographical associated reports, as vector control against Ae. aegypti Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 13 of 17 continues to be the corner stone in preventing dengue S-transferases; IGR: Insect growth regulator; kdr: Knockdown resistance; PBO: Piperonyl butoxide; PCR: Polymerase chain reaction; SNP: Single transmission and outbreak control. Bioassays are only nucleotide polymorphism; Vssc: Voltage-sensitive sodium channel; capable in detecting resistance that has already existed WHO: World Health Organization in a strain, while diagnostic assays can detect resistance Author details once it appears that this may avoid the failure in vector Tropical Infectious Diseases Research & Education Centre (TIDREC), management. Kdr assays have long been used for detect- 2 University of Malaya, 50603 Kuala Lumpur, Malaysia. Institute of Biological ing point mutations to observe the effect of control tac- Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia. tics on insecticide resistance, but it is crucial to note that these molecular assays of target site resistance Funding should also not replace bioassays until other resistance This study was funded by University of Malaya research grant (RP021D- 16SUS). mechanisms, e.g. metabolic resistance can be comple- mented by comparable assays. A major advantage of the Authors’ contributions molecular approach is that sequencing of Ae. aegypti CDC, MSA and VLL conceived the study. ZHAY conducted the review and drafted the manuscript. ZHAY and VLL wrote the final version of the genome aids in progressive study on insecticide resist- manuscript. All authors read and approved the final manuscript. ance mechanisms and further research should focus on searching for new diagnostic markers of pyrethroid Ethics approval and consent to participate Not applicable. resistance in dengue vectors. Biochemical assays in de- tecting enzymes linked to pyrethroid resistance have Competing interests been utilized in several Southeast Asian countries, be- The authors declare that they have no competing interests. cause these assays deliver important information for esti- mating resistance. However, the short of specificity and Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in sensitivity of some assays may lead to complications in published maps and institutional affiliations. analyzing data. As for the addition of synergists, such as PBO used to examine the significant of metabolic resist- Author details Tropical Infectious Diseases Research & Education Centre (TIDREC), ance, the protocol can be very problematic as a huge University of Malaya, 50603 Kuala Lumpur, Malaysia. Institute of Biological amount of alive Ae. aegypti populations will be needed. Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Hence, the above-mentioned challenge in biochemical Malaysia. assays are more difficult when analyzing the use of syn- Received: 7 March 2018 Accepted: 14 May 2018 ergist data. References Conclusions 1. World Health Organization. Dengue and severe dengue. 2017. http://www. 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Pyrethroid resistance in the dengue vector Aedes aegypti in Southeast Asia: present situation and prospects for management

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Copyright © 2018 by The Author(s).
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Biomedicine; Parasitology; Entomology; Tropical Medicine; Infectious Diseases; Veterinary Medicine/Veterinary Science; Virology
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10.1186/s13071-018-2899-0
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Abstract

Human arboviral diseases transmitted by Aedes aegypti such as dengue, Zika, chikungunya and yellow fever remain global public health threats to date. Of these diseases, dengue fever is particularly prevalent in Southeast Asia. Relentless vector control efforts are performed to curtail disease transmissions through which pyrethroid insecticides are broadly used as the first line of defense to control Ae. aegypti, especially in the course of disease outbreaks. Here, we compile the largest contemporary database for susceptibility profiles and underlying mechanisms involved in Ae. aegypti resistant to pyrethroids in Southeast Asia. The extensive use of pyrethroids inevitably elicit different levels of resistance to numerous populations despite the presence of geographical isolation. The most common mechanisms of pyrethroid resistance that have been identified in Ae. aegypti includes mutations in the voltage sensitive sodium channel gene (Vssc gene) and metabolic-mediated insecticide resistance. Aedes aegypti develops resistance to pyrethroids by acquisition of one or several amino acid substitution(s) in this Vssc gene. Enzymes involved in metabolic-mediated detoxification (i.e. monooxygenases, glutathione-S-transferases and esterases) have been reported to be related to pyrethroid resistance but many specific contributory enzymes are not completely studied. An inadequate amount of data from some countries indicates an urgent need for further study to fill the knowledge gaps. Perspectives and future research needs are also discussed. Keywords: Pyrethroids, Insecticide resistance, Knockdown resistance, kdr, Metabolic-mediated resistance Background insecticides and biological control. However, the most Dengue virus (DENV) and other arboviruses such as extensively practiced control for Ae. aegypti, owing to its Zika virus, chikungunya virus and yellow fever virus are high efficacy in regulating the populations with relatively transmitted by Aedes aegypti. This highly adapted spe- rapid action, is the application of chemical insecticides. cies thrives in urban and suburban areas. Effective con- The use of multiple classes of synthetic insecticides has trol of Ae. aegypti is absolutely challenging when this been largely practiced in vector control strategies, with species has deep-rooted and spread extensively in pyrethroid-based formulations massively dominating the disease-endemic regions. With a lack of safe and effect- insecticide market worldwide. ive treatment or vaccine for Ae. aegypti-borne diseases To the authors’ knowledge, there is no study to ad- to date, tactics in suppressing Ae. aegypti continue to be dress the overall prevalence of pyrethroid resistance in the cornerstone in preventing dengue transmission and Ae. aegypti in Southeast Asian countries. Therefore, this outbreak control. systematic review was carried out to determine related An effective vector prevention to transiently remove present situation to deliver datasets which will require in Ae. aegypti involves several strategies such as eliminating vector control management on improving public health potential mosquito breeding sites, applying chemical of human population. * Correspondence: ame_lia1031@hotmail.com; vanlun_low@um.edu.my Burden of pyrethroid resistance in Aedes aegypti Tropical Infectious Diseases Research & Education Centre (TIDREC), Geographical expansion of Aedes aegypti has fostered University of Malaya, 50603 Kuala Lumpur, Malaysia Full list of author information is available at the end of the article the incidence of dengue fevers (DF) to gain an apparent © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 2 of 17 increase worldwide, which put an estimation of almost character in implementing these programmes. However, it half of the world’s population at stake for the disease [1]. should also be stressed that the success of these pro- The most extensively practiced control for Ae. aegypti, grammes can only be accomplished if both parties are owing to its high efficacy in regulating the populations committed to implement procedures in assisting com- with relatively rapid action, is the application of chem- munity participation in Ae. aegypti control. ical insecticides [2]. Pyrethroid insecticides are currently being used extensively to control Ae. aegypti adults Pyrethroid resistance mechanisms worldwide and constitute approximately 17% of the Physiological resistance and behavioral avoidance of Ae. worldwide insecticide market share and 1.4 USD billion aegypti to insecticides are two integral responses as- of global trades [3]. In general, pyrethroids are neuro- cribed to the intensified implementations of chemical- toxins which modify the normal function of insect based control programmes. Physiological resistance im- nerves and cause disruption at the Vssc gene by depolar- plies the survival of mosquito victims under the expos- izing neurons [4, 5], paralyzing and eventually killing the ure to chemical insecticides which would normally lead insect. Deltamethrin, cypermethrin, cyfluthrin, lambda- to complete death, comprising the most well- cyhalothrin, permethrin, alpha-cypermethrin, pyrethrum, documented mechanisms conferring resistance against bifenthrin, d-phenothrin, z-cypermethrin and etofenprox pyrethroid insecticides in Ae. aegypti such as insensitiv- are the major types of pyrethroids used, and that their ity of target site which causes knockdown resistance treatments usually involve either residual or space spray (kdr)[19]; and metabolic detoxification via mixed func- [6]. Narrowing down to Southeast Asia, deltamethrin, per- tion oxidases (P450 mediated monooxygenases), ester- methrin, alpha-cypermethrin, cyfluthrin and lambda- ases and glutathione S-transferases (GSTs) [20]. cyhalothrin are commonly employed in suppressing Ae. Behavioral avoidance is the development of any change aegypti, particularly in Malaysia [7–9], Indonesia [10–12], in the behavior of a mosquito to decrease the exposure Singapore [13–15] and Thailand [16–18]. All the on- of toxic substances or to escape lethal effect of insecti- shelf insecticides available for vector control are cide, but this mechanism is easily overlooked [20]. Other obliged to apply cautiously to delay worldwide evolu- than the aforementioned resistance mechanisms, insecti- tion of mosquito resistance. cide resistance in Ae. aegypti is also mediated by cuticu- Currently, insecticide resistance is one of the most se- lar resistance. Notes on each mechanism are described vere issues facing mosquito control agencies. The loss of as follows. efficacy of pyrethroids may consequently bring high pos- sibility of operational failure of Ae. aegypti-borne dis- eases control and subsequently lead to increased disease Behavioral avoidance transmission. This will cause even larger capital to be In-depth behavioral avoidance studies in Ae. aegypti invested into mosquito control programmes by the gov- are scarce across Southeast Asia until now. A change ernment in return, for examples, the development of in mosquitoes’ feeding or resting behavior to new insecticides in terms of labors and costs, which may minimize exposure to insecticides, this mechanism is cause direct socio-economic impact to a country. Other generally categorized into direct contact excitation than the commonly-reported adverse impacts on public and non-contact spatial repellency [20]. Direct contact health and environment, reports particularly on the eco- excitation (irritancy) is a phenomenon when mosqui- nomic cost of pyrethroid resistance in Ae. aegypti in toes escape from insecticide-exposed environment Southeast Asia have not been presented. This is in large upon physical contact, while non-contact spatial re- part due to the progression of operating and resource pellency is when mosquitoes leaving the toxic area costs throughout the vector control programme since even before getting contact with a treated surface. Re- the first occurrence of control problems until complete lated behavioral avoidance studies of Ae. aegypti ex- control failures have not been described. To expedite the posed to a range of pyrethroids have been inspected progress and execution of scientifically-sound policies of in Thailand, projected that average to strong irritancy insecticide use, economic costs in Southeast Asian con- have demonstrated in all tested populations when text are vital to be studied. compared to repellency [21–24]. Despite the import- A need of new paradigm or choice to control Ae. aegypti ance of behavioral responses of mosquitoes to insecti- is undeniably urgent, provided that the current vector con- cides contribute to the efficacy of chemicals, the trol strategies in Southeast Asia resulted in the discovery of relative complications of the assay designs, for in- insecticide-resistant mosquito populations. The ultimate stance, problems in differentiating between contact goal of a vector control programme should focus on the es- excitation and non-contact spatial repellency re- tablishment of an efficient government-community sponses exerted in mosquitoes, lacking ideal statistical partnerships that the community plays a fundamental methods in analyzing data, and difficulties in Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 3 of 17 introducing and removing test specimens, cause a detected in Southeast Asia; for examples, S989P, dearth of information in this mechanism. I1011M/V, V1016G/I and F1534C based on the mutation positions of house fly sodium channel [10, 37–41]. It is Cuticular resistance no surprise that more sodium channel mutations in re- Cuticle thickening is implicated in insecticide resistance sistant insects have been discovered taking the advantage by reducing the uptake of the insecticide that reaches of the convenience of molecular approach. Beside the the target site in response to the modification of chem- identification of single point mutations, novel co- ical composition of the cuticle. In mosquitoes, cuticular occurrence of mutations was also detected. As firstly resistance is often pointed out but related studies are in- reviewed by Brengues et al. [37], V1016G was closely re- sufficient. A recent study revealed that this mechanism lated to S989P in Southeast Asian countries such as may play a major role in the development of resistance Indonesia, Myanmar, Thailand and Malaysia [9, 10, 39, 42], where it normally happens simultaneously with other and this common phenomenon was believed to confer mechanism(s) [25], causing resistance to single or mul- higher resistance. Co-occurrence of triple mutations tiple insecticides [26]. It has been reviewed elsewhere V1016G, S989P and F1534C would result in even higher that cuticle thickening is associated with metabolic de- resistance to pyrethroids, as seen in Ae. aegypti populations toxification whereby thicker cuticle causes gradual in- from Myanmar [39]. The detection of these specific muta- secticide absorption rate that will increase the tions, such as V1016G, S989P and F1534C, were affirmed effectiveness of metabolic detoxification in Anopheles to confer sodium channel resistance to pyrethroids and funestus [27]. Moreover, it is crucial to take note that in- other associated mutations which are still yet to be sects with cuticular resistance will display resistance inspected. It is very likely for the emergence of new kdr level of not more than 3-fold in comparison to suscep- mutations when pyrethroids remained to be the primary tible insects, but the co-occurrence of other resistance insecticide-based interventions in the control of Ae. aegypti. mechanism will lead to a surge in insecticide resistance Hence, these detections act as a crucial role in resistance level markedly [28]. This is demonstrated by Anopheles management of Ae. aegypti by observing the occurrence of gambiae in Benin [29] through which overexpression of pyrethroid resistance. cuticular genes and P450 genes gave rise to a relatively It is remarkable that despite two distinct substitutions high resistance level. Cuticular resistance to pyrethroids occur at the same amino acid position, V1016G and is also characterized in Ae. aegypti [30] but there is a V1016I display different geographical variations with dis- lack of similar report documented in Southeast Asia. similar response of Ae. aegypti sodium channel to pyre- The fact that this least-understood mechanism may play throids. V1016G has been detected in Southeast Asia substantial role in resistance urges for immediate atten- [37, 39, 40, 43, 44] while V1016I has been found in tion in investigating, particularly in pyrethroid-resistant North and South America [45–47]. In recent times, the Ae. aegypti. V1016I mutation was detected in Vietnam [41] and V1016I along with F1534C was detected in Ghana that Knockdown resistance (kdr) there may be presence of migration event [48]. The de- Target site resistance in mosquitoes is related to either tection of these point mutations in Ae. aegypti strains in single or multiple mutations in target genes; for ex- continents they have never existed before requires fur- ample, the Vssc gene which leads to kdr, mutations in ther validation to confirm if the resistance is caused by the acetylcholinesterase (Ace-1) gene and GABA recep- migration or de novo (new) mutations. The evolution tors [31, 32]. The most well-studied target site resistance and distribution of pyrethroid resistance in Ae. aegypti for Ae. aegypti is kdr because it confers resistance populations is relevant when their eggs can endure des- against pyrethroids. The Vssc gene comprises four hom- iccation for an extended period that permit them to put ologous domains and each of them contains six hydro- human travel to good use. phobic subunits (segments 1–6). In the past few decades, numerous mutations in the Vssc gene have Metabolic-mediated insecticide resistance been documented to be linked to kdr in many insect dis- Metabolic resistance in Ae. aegypti involves alterations ease vectors. The single point L1014F mutation in the in a series of the expression of a complex group of en- domain II segment 6 (IIS6) was the foremost mutation zymes, causing a rise in the detoxification process of in- associated with pyrethroid resistance identified. There- secticides. This resistance mechanism facilitates after, different substitutions of C, F, H, S or W at this increased biodegradation of insecticides, with the help of position have been reported in a few mosquito species in enzymes such as GSTs, esterases and cytochrome P450 the genera of Anopheles and Culex mosquitoes [33–36]. monooxygenases (P450 genes). A total of 160 P450 In Ae. aegypti mosquitoes, L1014 has yet to be identi- genes, 49 GSTs and 26 esterases have been revealed in fied but several different kdr mutations have been an international genome project of Ae. aegypti [49]. Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 4 of 17 Among these, cytochrome P450 genes are the enzyme of the enzyme family are still largely unverified up to family highly responsible for the development of pyreth- now especially in Southeast Asia. roid resistance in Ae. aegypti. Therefore, cytochrome It is indisputably important to investigate metabolic- P450 genes are of interest to study since they are capable mediated insecticide resistance of Ae. aegypti to pyre- in metabolizing xenobiotics such as drugs, plant toxins throids since co-existence of more than one mechanism is and insecticides. One of the most noteworthy character- likely to occur, especially the largest endemic sites of DF istics of P450 genes linked to enhanced metabolic de- Southeast Asia. In addition, efforts should be put in to the toxification of insecticides is the detection of a development of new insecticides, taking these enzymes re- significant rise in P450 proteins and P450 activity due to lated to insecticide resistance into consideration in the the overexpression of insecticide-resistant insects P450 span of design procedure. genes, which is closely associated with the development of insecticide resistance [50, 51]. However, identification Present situation of pyrethroid susceptibility in of enzymes associated with insecticide resistance is diffi- Aedes aegypti in Southeast Asia cult because of the presence of diverse group of P450 Published literature with regards to the insecticide resist- genes and high structural similarity in isoforms that ance profiles of Ae. aegypti against pyrethroids in most of makes identifying isoform related to resistance to be the Southeast Asian countries are detailed as follows. In- challenging. While molecular approaches in detecting formation were extracted from all publications document- Vssc gene mutations in pyrethroid-resistant Ae. aegypti ing mortality, lethal concentration (LC ) and knockdown are broadly documented, they are rare for P450 genes. time (KT ) from bioassays of Ae. aegypti mosquito popu- CYP9 family has been involved in pyrethroid resistance lations using merely pyrethroids. Since our main emphasis in the dengue vector Ae. aegypti [52]. CYP9J22 and was chiefly placed on studies assaying pyrethroids against CYP9M9 were the two P450 genes found with the high- Ae. aegypti, other classes of insecticides tested and species est transcript level of the resistant populations [52]. On other than Ae. aegypti found in the same publication were a global scale, the most frequently found P450 genes are excluded and not reviewed in this study. Kdr assays used CYP9M6, CYP6BB2, CYP9J26 and CYP9J28, which are to observe the effect of control tactics on pyrethroid re- commonly detected to be overexpressed in resistant sistance were also studied. Distribution of different kdr strains in many studies, projecting their capability in me- mutations in Ae. aegypti in Southeast Asia are summa- tabolizing permethrin [25, 53, 54]. rized in Table 1. Approaches employed to detect insecti- Esterase hydrolysis of pyrethroids resulting in the de- cide resistance when it first presents may allow timely toxification process has assumed to involve in metabolic associated management actions. Since there is a deficiency resistance in some cases. This mechanism encompasses of studies on the metabolic resistance in some of the a series of reaction, such as gene amplification, upregula- Southeast Asian countries, genes identified as overex- tion, and/or coding sequence mutations. However, pub- pressed in resistant populations are reported only in coun- lished data on which exact esterases in contributing to tries with related publications. Publications from all years the presence of pyrethroid-resistant Ae. aegypti popula- were retrieved, considered and incorporated into the re- tions in Southeast Asia continues to be scarce. Elevated view. Knowledge gaps which required attention are also levels of GSTs are also commonly associated with in- identified in this review. secticide resistance. Most of the GSTs are made of a super family structure of cytosolic-dimeric enzymes that Cambodia are grouped into a total of six classes, namely Delta, Ep- Although dengue is a major health concern in Cambodia silon, Omega, Sigma, Theta and Zeta [55]. The two lar- [57], there are merely two known studies evaluating in- gest classes of GSTs for insects are Delta and Epsilon, secticide resistance status of Ae. aegypti in the country. provided that Epsilon class is often involved with resist- The first related study was carried out using temephos ance [56]. In Ae. aegypti, there are basically a cluster of (an organophosphate) at Phnom Penh and Kampong eight sequentially arranged genes that mapped genetic- Cham in accordance with WHO standard bioassays [58]. ally to chromosome 2, supercontig 1.291 in the Epsilon Mosquito populations from Phnom Penh revealed teme- GST class [56]. Recently, microarray studies have discov- phos resistance whereas the latter populations were sus- ered some additional members of this gene cluster with ceptible [58]. It is believed that temephos resistance in elevated levels in Ae. aegypti populations resistant to in- Phnom Penh populations led to another more compre- secticides [52]. However, their roles in metabolizing in- hensive study encompassing Phnom Penh, Siem Reap, secticides like pyrethroids are yet to be determined. Kampong Cham and Battambang using both temephos Although esterases and GSTs are usually found overex- and pyrethroids (permethrin and deltamethrin). Resist- pressed in pyrethroid-resistant Ae. aegypti, the causal of ance to permethrin and deltamethrin were reported in specific enzymes to the resistant populations from each Ae. aegypti populations from all the aforementioned Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 5 of 17 Table 1 Distribution of different kdr mutations in unreported point mutations of the kdr gene. This helps Ae. aegypti in Southeast Asia to understand the nature of pyrethroid resistant in Ae. Country Mutation Reference aegypti in this country, given that dengue is endemic year-round in Cambodia. Biochemical mechanisms of Cambodia F1534C [60, 61] Ae. aegypti to pyrethroid resistance have not been V1016G [61] reported. Indonesia V1016G [10, 37, 44, 61, 63, 66] F1534C [10, 44, 61, 63, 66] Indonesia S989P [10, 44, 63] After a first occurrence in 1968, countless outbreaks of V1016G/S989P [10, 44, 63] DF and dengue haemorrhagic fever (DHF) cases trans- mitted by the primary vector Ae. aegypti mosquitoes Laos V1016G [43] have dramatically increased in recent years. The latest F1534C [43] statistic showed 71,668 DF human cases in 2015 [62], Malaysia V1016G [9] covering all 34 provinces of the country. In Indonesia, F1534C [9] pyrethroids have been broadly used since the 1980s Myanmar V1016G [39, 61] against Ae. aegypti but there has been a dearth of know- S989P [39] ledge on published information. Earlier, some pioneer works reported that Ae. aegypti populations from West F1534C [39, 61] Java (Ciamis, Purwakarta and Bogor) and Bandung were V1016G/S989P [39] resistant to permethrin, lambda-cyhalothrin, cyperme- V1016G/F1534C [39] thrin and d-allethrin [11, 37]. Despite high LT values V1016G/F1534C/S989P [39] being recorded [11], their resistant status regrettably Philippines na should not be concluded. The standard susceptible la- Singapore F1534C [25, 93] boratory strain used as a control in the study appeared to be resistant, led to an uncertainty of the resistant sta- V1016G [25, 40, 93] tus. More recently, published data showed the presence Thailand I1011V [40] of pyrethroid resistance in Ae. aegypti even after ap- F1534C [60, 61, 108] proximately 10 years of the pioneer studies [10, 44, 63]. S989P/V1016G [42, 112] Their susceptibility profiles suggested similar trends of V1016G [37, 40, 61] resistance to pyrethroids [10, 44, 63], signifying compar- V1016G/F1534C/S989P [109] able patterns of insecticide usage in these sampling sites. Over the years, biochemical studies have acknowl- Timor-Leste na edged the role of detoxifying enzymes in the develop- Vietnam V1016I [41] ment of pyrethroid resistance in Ae. aegypti. The first I1011V [126] small-scale test in determining the resistance mecha- F1534C [126] nisms involved in pyrethroid-resistant Ae. aegypti was V1016G [126] accomplished in 2007, comprising strains from Bandung, Abbreviation: na, not available Palembang and Surabaya [12]. Adult Ae. aegypti from Bandung demonstrated the highest resistance level to study sites [59]. Therefore, a nationwide assessment is both permethrin and deltamethrin, corresponding to the recommended to examine pyrethroid resistance in Ae. high levels of activity of enzymes tested, i.e. oxidases, es- aegypti since Cambodia is a country bordering the terase A and esterase B, that play roles in the develop- dengue-endemic countries Thailand, Laos and Vietnam, ment of resistance to pyrethroids. In contrast, another so as to develop effective vector control methods to halt study [64] showed that larvae from most sampling sites the spread of DF. in Cimahi were still susceptible to pyrethroids although In Cambodia, the point mutations of the kdr gene re- Bandung situates in absolutely close proximity to lated with pyrethroid resistance of Ae. aegypti were ana- Cimahi. Adult susceptibility profile may greatly correlate lyzed alongside with samples from other Southeast Asia with larval susceptibility profile in some cases [7, 65]. countries in two international studies. The F1534C mu- However, it should be remembered that there is a differ- tation was detected in the first study [60] whereas ence between resistance score in larvae and adults be- C1534 mutant alleles (with VV/CC patterns) were de- cause they may develop dissimilar resistant mechanisms tected in the second study [61]. Further detection is through different mechanism pathways from larval to highly sought after due to a deprived of nationwide stud- adult stages [14]. Thus, adult bioassay is still required to ies that may possibly lead to the discovery of other verify the resistance status. Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 6 of 17 Other than the responsibility of detoxifying enzymes in control after the official ban of DDT in 2010 [70], the insecticide resistance mechanisms, mutations in the more comprehensive studies are needed in Laos, as Vssc gene should also be highlighted because they may act this knowledge is fundamental in managing vector as markers for resistance monitoring. In Indonesia, kdr control programmes. profiling of Ae. aegypti had recorded three point mutations related to pyrethroid resistance, namely the S989P, V1016G Malaysia and F1534C mutations [10, 37, 44, 63, 66]. The discovery DF or DHF has been a critical public health concern in of the V1016G mutation was first reported by Brengues et Malaysia at all times since the first outbreak in 1973. Re- al. [37] in the Semarang strain. Later, some findings were gardless of extensive fogging operations with malathion in agreement that all three mutations in Vssc gene were de- in Malaysia as early as the 1970s, and followed by the re- tected in Ae. aegypti populations from Yogyakarta, Central placement of pyrethroids like permethrin and deltameth- Java Province, Denpasar and Jakarta [10, 44, 63, 66]. The rin in early 1998 until today [71], dengue remains V1016G mutation was most frequently detected in high number one infectious disease with a total of 101,357 frequencies, remarkably associated with permethrin and cases reported in the country [72]. Numerous surveil- deltamethrin resistance in Ae. aegypti. Previous reports dis- lance activities have been conducted to investigate in- covered relatively low frequency of the F1534C mutation, secticide susceptibility status of Ae. aegypti. The first which did not demonstrate significant contribution to the study examining on the pyrethroid resistance level of Ae. resistance development of pyrethroids in Ae. aegypti aegypti in Malaysia was accomplished in 2001, using [10, 44, 63, 66]. As for the S989P point mutation, it field strains from Kuala Lumpur, Selangor, Negeri Sem- generally co-occurred with the V1016G mutation, bilan, Johor, Kelantan and Pahang. The urban strain of showing association on pyrethroid resistance develop- Ae. aegypti from Kuala Lumpur showed the highest re- ment in Ae. aegypti. Furthermore, the frequency of the sistance to permethrin, validating the high levels of es- V1016G mutation occurred in Ae. aegypti in the Cen- terase compared to the laboratory strain [73]. This result tral Java has increased two-fold in just a decade, com- was in agreement with the findings performed after al- pared to a report generated earlier [37]. These most a decade. Permethrin resistance persisted in field preliminary detections of insecticide resistance will fun- strains of Ae. aegypti collected from dengue-endemic damentally aid in initiating appropriate control mea- areas of Kuala Lumpur [7]. Both larval and adult bioas- sures in delaying development of mosquito resistance, says of the field strains confirmed the development of for instance rotation of insecticide or addition of cata- tolerance towards permethrin with several folds higher lyst to enhance the efficacy of insecticides in suppress- than the laboratory strain [7], indicating high reliability ing Ae. aegypti in Indonesia. on chemical insecticides to control Ae. aegypti in an un- precedented scale at the dengue hotspots. Piperonyl but- Laos oxide (PBO) was also reported to be effective in Compared to the neighboring countries, there is a enhancing the effectiveness of permethrin through scarcity of study on pyrethroid resistance in Ae. which strong correlations were confirmed between LC aegypti in Laos. The first DF outbreak was recorded or LT values and oxidase levels for all strains [7], im- in 1998 in Khammouane Province [67]. Although plying the involvement of oxidase activity in causing per- Ae. aegypti has been stated to be the main vector methrin resistance in this mosquito species. of numerous mosquito-related diseases in Laos Another similar study performed at dengue-prone sites [67, 68], with 22,772 cases of dengue reported dur- of Selangor documented resistance and incipient resist- ing 2010 [69], there is only a single report investi- ance of Ae. aegypti to permethrin (mortality ≤ 80%) and gating pyrethroid resistance status of Ae. aegypti in cyfluthrin (mortality 45–97.8%), respectively [8]. Al- the country thus far. Samples were collected from though cyfluthrin was not used by the municipal in vec- five provinces and populations involved in the study tor control programme, fluctuated resistance was identified high level of resistance against permeth- detected and this may be attributed to the role of kdr. rin, which contrast with deltamethrin that exhibited Screening of kdr is yet to be performed in Selangor but high susceptibility in Ae. aegypti [43]. Higher quan- it has already accomplished and confirmed on the pres- tities of P450 genes were detected in field compared ence of kdr in Kuala Lumpur [9], which is very close to to reference strains but no particular CYP was Selangor. DDT resistance was also detected over the mentioned. The frequencies of kdr mutations were course of the study [8], further supporting the role of low for the V1016G mutation (< 0.36) but relatively kdr in both pyrethroid and DDT resistance due to the higher for the F1534C mutation (> 0.6 for majority shared Vssc target site. GST activity exerted on DDT re- of places). With a total of 18 provinces available in sistance has not been discovered in Malaysian mosqui- Laos and a reliance upon pyrethroids in Ae. aegypti toes including Ae. aegypti [71, 74]. The widespread of Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 7 of 17 insecticide resistance pays full responsibility to failures w/w of d-trans allethrin were proven to show higher in vector control programme. Aedes aegypti populations repellent efficacies and mortality [82]. However, this re- from mainland Penang were also highly resistant to sult requires further verification on field strains in nat- lambda-cyhalothrin [75]. These outcomes were sup- ural settings. In the past decades, efficacy studies were ported by the fact that pyrethroids have been broadly performed on the laboratory strains of Ae. aegypti. Until sprayed in the study areas for more than 10 years. Of recently, insecticidal activities of Malaysian commercial several studies conducted in the country, insecticide sus- coils have been assessed on field strains of Ae. aegypti in ceptibility status of permethrin was often tested against a nationwide-scale. Aedes aegypti from a total of 11 Ae. aegypti in Malaysia because this insecticide is one of states were discovered to be resistant to mosquito coils the main adulticides used in Malaysia [76]. Moreover, containing active ingredients of d-allethrin, d-trans alle- the development of permethrin resistance at a higher thrin, metofluthrin and prallethrin, according to the re- rate than malathion and temephos [77] might be closely sistance index recommended by the WHO [83]. Since associated with gene activation due to the exposure to there is a wide array of insecticides used intensively in insecticidal pressure. the country to curtail disease transmission, either opera- More recently, despite discrepancies of insecticide sus- tions conducted by the Ministry of Health, private com- ceptible status found in the field strains of Ae. aegypti panies or even at household level [84], it is utmost from Kuala Lumpur, Penang, Johor Bharu and Kota important to assess regularly on the efficacies of insecti- Bharu tested against permethrin and deltamethrin, the cides used to guarantee effective vector control mosquito strains from Kuala Lumpur remained to ex- programme. hibit the highest resistance levels [9]. Synergist assays with PBO showed that metabolic resistance mechanisms Myanmar played key role in certain strains. This particular study is The first documented outbreak of DHF was in 1969 and the first report in Malaysia in characterizing the kdr re- then the outbreaks gradually increased to 12 out of 14 sistance in Malaysian populations of Ae. aegypti. The states in Myanmar [85]. This disease was documented V1016G and the F1534C mutations were detected, with with a high of 83,381 cases, causing 3243 deaths be- the F1534C mutation closely associated with pyrethroid tween 1970–1991 [85]. No sign of decrement in DHF resistance whereas the V1016G mutation co-occurred to incidence with 5621 cases in 2005 to an approximate contribute to the additive effect of pyrethroid resistance two-fold of 11,049 cases in 2006 [86], despite persistent in Malaysia [9]. A microarray-based genome-wide tran- control efforts made by the Myanmar government since scriptional analysis discovered that metabolic resistance 1968 [85]. Although the significance of the disease re- of pyrethroid resistance in Ae. aegypti populations is quires immediate attention, there is only a single report predominantly caused by overexpressed of the cyto- on the ecological study of Ae. aegypti focusing on the chrome P450 genes (CYP9J27, CYP6CB1, CYP9J26 and southern part of Myanmar [86]. There is still an unavail- CYP9M4)[32]. However, more characterization work on ability on the bioassay studies of the status of pyrethroid the cytochrome P450 family must be carried out to resistance in Ae. aegypti in the country. understand the precise roles of these genes in contribut- There is an absence of study to date, regarding the ing pyrethroid resistance in Ae. aegypti. biochemical mechanisms of Ae. aegypti to pyrethroid re- As far as we know, Malaysia is one of the two coun- sistance. In 2014, a project was initiated to evaluate the tries in Southeast Asia tested on the efficacies of the types and frequencies of point mutations of the kdr gene commercial mosquito coils against Ae. aegypti. The mos- related with pyrethroid resistance of Ae. aegypti.Itwas quito coil is one of the most extensively-used anti- revealed that V1016G and S989P mutations were exten- mosquito household spatial repellents in Malaysia, ac- sively scattered in Yangon city with high frequencies of counting for the low costs and easy availability on-shelf 84.4% and 78.8%, respectively [39]. Another widely scat- countrywide [78–81]. In 1996, the first study assayed on tered point mutation identified with relatively low allelic the efficacies of mosquito coils containing active ingre- frequency of 21.2% was F1534C [39]. Other than three dients like d-allethrin (0.2% w/w) and d-trans allethrin single point mutations were detected in Yangon city, (0.1% w/w) against laboratory Ae. aegypti were accom- three patterns of co-occurrence of point mutations were plished, revealing adequate knockdown effects but with also identified with widely distributed homozygous minimal mortalities for both coils [78]. After almost a V1016G/S989P mutations (65.7%), as well as a small num- decade, a similar study was conducted with the use of ber of homozygous V1016G/F1534C mutations (2.9%) d-allethrin (0.2% and 0.3% w/w) and d-trans allethrin (0. and homozygous V1016G/F1534C/S989P (0.98%) [39]. It 1% and 0.2% w/w) on laboratory strain of Ae. aegypti should be noted that the observed types and frequencies [82]. Dosage increment of the active ingredients in mos- of resistance alleles may be very well representing the Yan- quito coils, which are 0.3% w/w of d-allethrin and 0.2% gon city, as samples were collected from seven townships. Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 8 of 17 However, it may not be a decent approximation of types ever since they were first introduced in Singapore. The and genotype frequencies of the country because the size use of synergists (piperonyl butoxide, S,S,S,-tributyl of Yangon city (598.75 km ) is relatively small compared phosphorotrithioate, and triphenyl phosphate) was also to Myanmar (676,578 km ). Therefore, sampling is needed deemed to be insignificant to the insecticides used in throughout the country to ensure the surveillance of these studies to increase toxicity, signifying negligible resistance genes in wild Ae. aegypti populations are roles of metabolic-based resistance when further bio- comprehended. chemical investigation discovered that detoxifying en- zymes such as monooxygenases, esterases, and GSTs Philippines failed to contribute to pyrethroid resistance [14, 15]. The There appears to be an agreement in literature that Ae. ineffectiveness of synergists proposes that molecular aegypti was introduced into the Philippines approaching work is recommended to further investigate the mecha- the end of 19th century and followed by the proliferation nisms contribute to the high pyrethroid resistance exhib- of this dengue vector [87]. However, there are only two ited in local Ae. aegypti. known studies evaluating the insecticide resistance of Other than fogging, space spraying, chemical treat- Ae. aegypti to pyrethroids in the Philippines. In the first ment and source reduction as dengue vector control study, Ae. aegypti from Luzon Island, Manila was con- methods, deltamethrin-treated net is an alternative. firmed to be susceptible to dieldrin even after eight years However, its efficacy was proven to be unsatisfactory of insecticide application in the country since 1959 [88]. against field Ae. aegypti in a recent study [93]. Three Currently, the latest susceptibility test of Ae. aegypti with molecular investigations have evaluated the roles of indi- the use of pyrethroid was completed in 1997 in Cebu vidual and multiple Vssc gene mutations in contributing city. It was proven that treatment of curtains with per- to the developed pyrethroid resistance in Singaporean methrin was an effective vector control measure [89]. Ae. aegypti: F1534C, S989P+V1016G and F1534C These preliminary studies facilitated in verifying the de- +V1016G [25, 93, 94]. However, in-depth study showed velopment of resistant strains in the country but the in- that G1016 alleles independently pay more responsibility formation may not be up to date, and related studies are to Vssc gene insensitivity than C1534 alleles independ- recommended in the future because DF is endemic in ently [25, 94]. To the best of our knowledge, S989P neighboring countries like Malaysia. Susceptibility tests +V1016G+F1534C triple mutations in Vssc gene exhib- of different pyrethroids and related resistance mecha- ited in the local Ae. aegypti were first reported in nisms should be attempted on different field populations Singapore. They exerted the largest pressure in channel of Ae. aegypti in the country to confirm insecticide sus- sensitivity to permethrin and deltamathrin by 1100-fold ceptibility status and guarantee the representativeness of and 90-fold [94], implying the likelihood of reduced effi- the information generated since those insecticides have cacy to pyrethroid insecticides. There is also a need of been put to use for several decades. an immediate attention to monitor the occurrence of triple mutations in Vssc gene of field Ae. aegypti popula- Singapore tions worldwide, so that the challenge of mosquito vec- It is clear that Ae. aegypti mosquitoes are the primary tor control will not further exacerbated. The significance vectors of DF in Singapore, with the first dengue case re- of P450-mediated resistance is mirrored by the highly- ports in the 1960s [90]. In the 1970s, pyrethroids were resistant Ae. aegypti Singapore (SP) strain, showing first introduced to the country to deprive the popula- 1,650-fold of resistant to permethrin and PBO has re- tions but permethrin resistance was identified in field duced the resistance by 48-fold [25]. P450 genes Ae. aegypti later [91]. Subsequently, an assessment in (CYP4C50, 6BB2, 6F2, 6F3, 6Z7, 6Z8, 9M4, 9M5 and 1999 revealed a 12.9-fold of RR of field Ae. aegypti 9M6) were also discovered to be overexpressed in adult against permethrin [13]. Resistance of Ae. aegypti to females and males [25]. Precise and reliable molecular cypermethrin was also reported in a study between diagnosis approach to identify metabolic enzymes con- 2004–2007 [92]. More recently, the detection of resist- ferring pyrethroid resistance in Ae. aegypti populations ance of Ae. aegypti to pyrethroids were further verified should be emphasized to elucidate the contribution de- by two comprehensive nationwide insecticide resistance gree of P450 genes to field-resistant strains from distinct studies on larvae tested with permethrin and etofenprox, areas. as well as adults with cypermethrin, deltamethrin and etofenprox [14, 15]. Despite the a few decades of gap be- Thailand tween these studies, high resistance to pyrethroids Thailand is the country with the most studies evaluating remained to persist in the Singaporean Ae. aegypti popu- on the insecticide resistance of pyrethroids to Aedes lations and they continued to thrive, portraying the aegypti in Southeast Asia, reflecting a substantial geo- widespread or probably inappropriate use of pyrethroids graphical bias as this species is widespread in many Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 9 of 17 countries in this sub-region. Thailand first experienced irrefutably important when mosquito coils are the top outbreaks of dengue hemorrhagic fever in 1958 and the choice of household insecticide formulations worldwide disease has since then distributed nationwide [95]. To other than aerosols, vaporizing mats and liquid vaporizers. date, DF or DHF remain a severe health threat in The first report was completed in 2008 in Thailand, show- Thailand regardless of unrelenting vigilance in vector ing a phenomenon of tolerance of Ae. aegypti to dl, d- control programmes. Reliance has been on the carba- T80-allethrin, d, d-T-prallethrin and methoxymethyl-tet- mate, organochlorine and organophosphate insecticides rafluorobenzyl tetramethyl-cyclopropanecarboxylate (K- since 1950 [17] and the use of synthetic pyrethroids then 3050) under semi-field condition [103]. A similar study dominated the market since 1992. Pyrethroid-based for- was conducted with a total of four field strains of Ae. mulations with 12 distinct active ingredients are com- aegypti tested against the same active ingredients, employ- mercially available to all household levels countrywide to ing 25 m semi-field test system, topical application test control mosquitoes in response to their low price, quick and field efficacy test [104]. Most of the strains were re- knockdown effect and are relatively safe for human con- corded to be tolerant to the mosquito coils tested but pyr- tact because of low mammalian toxicity [17]. Years of ethroid resistance may have already developed since routine contact with these insecticides have induced noticeably large gaps were observed between the time- high levels of resistance in Ae. aegypti. frame of sample collection and the course of the study, To understand the insecticide susceptibility profile of with up to 31 years gap. It is recommended that, when Thai Ae. aegypti to pyrethroids, there have been several possible, mosquito test populations should be acquired published pioneering works available, but specific geo- with shorter gap to prevent bias in the outcomes. The lat- graphical restrictions were observed whereby they were est related study was accomplished in 2009 using 25 m conducted in small confined areas during previous de- semi-field test and topical application test, demonstrating cades. Increasing tolerance or resistance to different extremely low susceptibility to dl, d-T80-allethrin in some types of pyrethroids, namely deltamethrin, permethrin, field strains [105] and that they may have already devel- dieldrin, bioallethrin, bioresmethrin or alphacyperme- oped resistance now. All three studies yielded similar out- thrin, has been reported in larval and adult Ae. aegypti comes with low allethrin susceptibility, but it should be in Thailand [16–18, 96–101]. The absence of large scale noted that direct comparison of results should be avoided evidence-based understanding of the knowledge between due to different testing approaches used. Standardization the susceptibility profile and insecticides used may of method is needed to avoid significant data deviation largely hinder the effect of dengue control efforts. A from a study to another. The knockdown time may vary comprehensive study evaluating the insecticide suscepti- in regard to types of method employed, that according to bility level will aid in better efficiency in programme- Chadwick [106], results carried out in cylinders, small planning to target the disease vector. More recently pub- chambers and large rooms are distinct. Moreover, associ- lished data on pyrethroid resistance in Thai Ae. aegypti ated assessments on the efficacy of mosquito coil to Thai addressed the issue that all 32 strains of Ae. aegypti were Ae. aegypti are also needed. discovered to be resistant to permethrin, ranging A simple colorimetric assay based on Heated Oligo- between 4.0–56.4% [102]. The frequency of susceptibility nucleotide Ligation Assay (HOLA) kdr assay from past to deltamethrin in this species showed more than 98% of studies was developed to detect substitutions within do- mortality to deltamethrin in the majority of the popula- main II, subunit 6. i.e. Met1011, Val1011, Ile1016, and tions, with incipient resistance detected in minor popu- Gly1016 [40]. The V1016G mutation was evidently de- lations. Conversely, all 32 strains of Ae. aegypti were tected in high allele frequency of 0.23 throughout entirely susceptible to lambda-cyhalothrin with 100% Thailand in pyrethroid-resistant Ae. aegypti, and that the mortality. Significantly high levels of permethrin resist- I1011V mutation to be the minority with an allele fre- ance were documented by [18] (5% mortality) and [96] quency of 0.14 [40]. Despite only a thermal cycler being (2–9% mortality) which contrast with this particular involved in this assay, extra reagents are needed which study. This may attribute to the differences in sampling contributes to the increment of cost. An allele-specific sites and the alterations in levels of exposure to polymerase chain reaction (AS-PCR) assay was then de- permethrin. veloped to detect the V1016G mutation which was Personal protection tools, for instance mosquito coils, shown to be reliable [107]. Homozygous 1016G mosqui- are extensively used in Thailand but these products have toes were found to be common in Thailand and showed never been thoroughly studied. Although literature pre- higher survival rates than either heterozygous or wild- sents on the efficacies of commercially available mos- type (1016V) mosquitoes upon deltamethrin exposure, quito coils, up to now, information about detailed indicating this particular mutation confidently related to assessment on these coils to field populations of Ae. deltamethrin resistance. Subsequently, the F1534C mu- aegypti remains to be sparse. These studies are tation was discovered as a novel amino acid mutation in Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 10 of 17 2010 in permethrin-resistant Ae. aegypti, and was re- deltamethrin exposure earn further attentions. This ported to play a significant role in contributing permeth- overlaps the study of Somwang et al. [111], which de- rin resistance in multiple field strains [108]. The wide scribed oxidative enzyme systems also involve in pyreth- distribution of this mutation led to the development of roid resistance in Ae. aegypti in Thailand. Another study high-throughput molecular tools, namely TaqMan single showed that biochemical assays are very much required nucleotide polymorphism (SNP) genotyping and an AS- when a difference of low kdr resistant allele frequency of PCR assay, which proved to be consistent in detecting S989P and V1016G with high level of permethrin resist- the F1534C resistance mutation in the permethrin- ance was reported in field strains of Ae. aegypti, which resistance Ae. aegypti populations [108]. Recently, a this implies detoxification enzymes show the possibility multiplex polymerase chain reaction (PCR) was devel- to be involved in insecticide resistance mechanisms oped to detect both V1016G and F1534C kdr mutations [112]. in Ae. aegypti through a single-reaction protocol [61]. Biochemical assays used to detect enzymes metaboliz- This method was evidenced to depict high sensitivity ing insecticides have been available for over three de- and specificity in detecting the aforesaid kdr mutations, cades to monitor insecticide resistance of Ae. aegypti in enabling the monitoring of the frequency of mutant various countries. In Thailand, the first related study was alleles across dengue-endemic countries at ease with re- accomplished in 2002 using laboratory bred artificially duced time and cost. selected resistant Ae. aegypti. GST and esterase activities Other than the discovery of singly-occurred mutations, were detected to be only marginally higher relative to the novel co-occurrence of the S989P mutation and the the susceptible strain, signifying that both enzyme V1016G mutation were detected in Thai deltamethrin- groups show no major role in permethrin resistance resistant Ae. aegypti [42]. The 1016G mutation usually [113]. In contrast, the subsequent biochemical assay of coexists with 989P mutation but there is also an absence metabolic enzymes tested with field Ae. aegypti to pyr- of 989P mutation in some Thai populations which were ethroid resistance revealed esterase, monooxygenase and homozygous for 1016G [37]. Since some studies showed GST are closely associated with permethrin resistance that the V1016G mutation has been reported in the ab- whereas deltamethrin resistance is related to esterase sence of the S989P mutation, it is likely to hypothesize and monooxygenase [21]. Later, a number of studies that this point mutation acts as an additive mutation proposed that an elevated level of mixed function oxi- [42]. Furthermore, the V1016G/F1534C/S989P muta- dase was usually in association with pyrethroid resist- tions have been confirmed in Thailand, demonstrating ance [16, 114]. Moreover, considerable escalated levels of an additive effect on deltamethrin sensitivity which gives esterases and GSTs were stated in some field strains of high level of resistance [109]. Recent work has also em- pyrethroid-resistant Ae. aegypti [114]. The latest study phasized that the variations of point mutations exerted demonstrated that the aforementioned enzymes were ei- on pyrethroid-resistant Ae. aegypti revealed different re- ther unrelated or merely contributed partially in pyreth- sponse to insecticides. Thermal fogging spray with delta- roid resistance [115]. In regards to the discrepancies of methrin and PBO synergist killed all resistant genotypic these enzymes as contributory factors to pyrethroid re- mosquitoes in indoors [110]. In contrast, the outdoor sistance in Ae. aegypti, it should be noted that in vitro spray displayed minor impact on the G1016 homozygous experiments may not reflect the in vivo circumstances of mosquitoes, partially killed the G1016/C1534 double insect metabolizing insecticide molecules and thus, field heterozygous mosquitoes and triggered high mortality in studies including numerous variables should be consid- the C1534 homozygous mosquitoes [110]. Further asso- ered in the future. ciated studies should be conducted to understand other polymorphisms complementing the Vssc mutation and Timor-Leste how they are related to the resistance phenotype when Timor-Leste is not excluded from vector-borne diseases selection pressure is extrapolated to act on the survival transmitted by Aedes mosquitoes, due to its generally of pyrethroid-resistant Ae. aegypti. Moreover, further warm and humid climate which is conducive for their verification is also needed to make implications that the growth. Dengue cases were first reported in 2003, aforesaid mutations are linked to deltamethrin resist- followed by an outbreak resulted in 933 cases and 37 ance. Other than the target site insensitivity mechanism deaths in 2005 in Dili, Bobonaro and Baucau [116, 117]. acts upon the pyrethroid resistance in Ae. aegypti, a pre- Although Ae. aegypti was extensively spread in the vious study addressed the absence of the 1016G muta- country [116], there was only single international project tion in deltamethrin resistance mosquito strains and carried out, by Frances et al. [118] who employed bottle revealed the role of mixed function oxidases in confer- bioassay to examine insecticide resistance in Ae. aegypti ring the resistance [16]. Thus, the contributions of meta- and the respective biochemical mechanisms using pyre- bolic mechanisms in these wild-type individuals upon throids (permethrin, resmethrin, lambda-cyhalothrin). Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 11 of 17 These insecticides were in line with the other insecti- pronounced increment of resistance in Ae. aegypti to d- cides used more than a decade ago for vector control allethrin with decrease in the latitude of sampling sites programmes in the country as stated by Whelan & Petitt [125], corresponding to the findings of an earlier study [117]. Since pyrethroid resistance was detected in Ae. [124]. Analysis of point mutations was further investi- aegypti collected from a single site in Dili with elevated gated and the F1534C mutation was verified to be the levels of esterases, there is a need in investigating the ef- chief point mutation that gave rise to high resistance in ficacies and mechanisms contributed to the resistance of the specimens collected from the South, whereas the pyrethroids towards the Ae. aegypti populations in heterozygous V1016G mutation was very low in fre- Timor-Leste. quency [126]. Although low frequencies were detected in the North and the percentage of homozygous F1534C Vietnam remained low (7.4%), unrestrained use of photo-stable DHF was first documented in Hanoi, Vietnam in 1958 pyrethroids that persists in the environment may induce [119], followed by the first and second outbreaks recorded selection pressure for this point mutation, which will re- in 1960 and 1963, respectively, in South Vietnam [120]. sult in more resistance offspring. With 21,000 liters of Vietnam, like all the other Southeast Asian countries, uti- pyrethroids used in dengue control operations in 20 lizes chemical insecticides as the primary tool in ceasing southern provinces in 2007 [127], it is no surprise that spread of the vector of DHF, Ae. aegypti. Although Ae. Ae. aegypti populations from Vietnam have developed aegypti was introduced to the country in 1915 [121]and insecticide resistance. Therefore, the use of PBO as a DHF has been reported to be endemic in Vietnam for synergist was considered to increase the efficacy of detal- decades [122], there are insufficient amount of studies methrin to Ae. aegypti from Nha Trang [41]. The study available in evaluating the efficacies of pyrethroids to Ae. subsequently proved that synergists might play crucial aegypti and their related mechanisms [41, 122–126]. role in Ae. aegypti control programme [41]. Moreover, The first insecticide resistance study of Ae. aegypti was Nha Trang strain housed multiple resistance, the overex- conducted in 1998 and 1999, showing that the mosqui- pressed P450 gene CYP9J32 relative to the susceptible toes were resistant to few pyrethroid insecticides in sev- strain was found capable in metabolizing deltamethrin eral locations of Central Highlands and Nam Bo [122]. effectively, as well as two homozygous kdr mutations Later, a similar but more comprehensive study was com- which were the I1011V (100%) mutation and the V1016I pleted in 2004, encompassing four regions of Vietnam, (67%) mutation. Attention should be paid to the detec- and revealed that Ae. aegypti from numerous locations tion of the V1016I mutation in Vietnam when this point in the Centre and North regions were susceptible to py- mutation was only circumscribed in the continent of rethroids but those from South and Central Highlands America in the past [38, 45, 128]. Thus, consistent mon- were more resistant [124]. This was believed to be re- itoring of insecticide resistance is required. lated to the frequent and prolonged use of pyrethroids in the highlands for the Ae. aegypti control programme Future challenges and perspectives [124]. Apart from the aforementioned factor that may When development of resistance has become a world- influence the susceptibility status of Ae. aegypti to pyre- wide issue, there are alternatives to control Ae. aegypti. throids, mosquitoes from places with high populations Environmental control in Southeast Asia involves source develop higher resistance than those from outskirts; Hu- reduction and the use of mosquito traps or screen net ber et al. [123] showed that Ae. aegypti in cities with covers [129–132]. Standing water and unnecessary con- high populations, like Ho Chi Minh City, developed tainers, in both indoor and outdoor conditions, should higher resistance than those from the outskirts or Long be eliminated to prevent breeding of mosquitoes, specif- An Province. Other than inspecting previously reported ically Ae. aegypti and other container breeders [79]. dengue hotspots, these pioneer studies provided insights Containers that performed functions in daily life should into pyrethroid resistance in Ae. aegypti and reported be screened or properly covered. Source reduction that Ae. aegypti populations in the country had already should also include getting rid of natural habitats that developed resistance to some pyrethroids. collect water, such as bamboo stumps and tree holes to The most extensive nationwide assessment of pyreth- avoid the breeding of Ae. aegypti. roid resistance in Ae. aegypti was completed in 2009, ap- To diversify the choices of vector control, research has proximately a century after this disease vector made its been reinforced in developing pathogenic organisms to way to Vietnam. A total of 527 collection points were in- combat dengue vector. In biological control, natural en- volved from northern to southern Vietnam [125]. A sim- emies are either predators, microbes or parasites [79]. ple bioassay of fourth instar larvae using glass vials was Examples of biological control in Southeast Asia include developed to detect knockdown susceptibility [125]. The the participation of predaceous aquatic insects as natural most notable outcome of this study demonstrated a enemies to suppress mosquito populations by predating Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 12 of 17 on mosquito larvae as food source [57, 133, 134] or the distribution in published reports with more than half use of the entomopathogenic bacteria Bacillus thurin- published from Thailand, Indonesia and Malaysia. Al- giensis var. israelensis to destroy the gut lining of mos- though studies retrieved from the database reflected the quito larvae [130, 135]. Hypothetically, predaceous burden of DF, it is believed that some dengue-endemic animal species should result in reduction of mosquito countries such as Vietnam and Myanmar may have re- populations, but there is limited evidence regarding tan- stricted the accessibility of the database without releas- gible proof of related declining disease burdens. There- ing to the public. This leads to difficulty in deciding on fore, it should be noted that these methods would work suitable insecticides for dengue control and, therefore, a well alongside chemical insecticides but should never be platform with insecticide resistance status of different employed as a sole control tactic during epidemic out- Ae. aegypti populations in a homogenous format would breaks of dengue when immediate elimination of disease critically solve related challenges and ease future vector vectors should be prioritized. control planning. In certain cases, uniformity of proto- Another biological control method involves the release cols was neglected. Examining the broad range in the of Ae. aegypti infected with Wolbachia. These naturally- methodologies utilized to record and analyze resistance occurring bacteria infect a wide range of arthropods and or susceptibility data of various studies is very challen- nematodes but are absent in Ae. aegypti [136]. To de- ging. Thus, only some attempts were made to specify crease dengue transmission, Wolbachia from naturally the level of susceptibility that the standardization of infected organisms are vertically transmitted into Ae. methods in all of the studies would contribute to reliable aegypti. This causes sterility via cytoplasmic incompati- comparison of the outcomes. Method of recording in- bility, resulting in eggs without progeny when an secticide resistance should be consistent, taking LC / uninfected female Ae. aegypti mates with a Wolbachia- LT /KT or other similar set of data for instance, 50 50 infected male [137]. Wolbachia has drawn much atten- though actual values may still have to be provided for tion and field trials are ongoing in several countries such comparison in some circumstances. as Australia [138], Vietnam [139] and Indonesia [140]. In addition, the use of the revised version of World Despite wMel Wolbachia showing positive result in low- Health Organization (WHO) guidelines was not prac- ering the incidence of dengue in human populations in ticed in all the studies. WHO has initially published two northern Australia [138], wMelPop Wolbachia with even different databases on the diagnostic dosages of distinct more significant resistance to DENV infection failed to insecticides [142, 143]; there are still some studies that establish successfully in Australia and Vietnam. Hence, employed the original diagnostic doses to examine the more progressive studies pertaining to the large-scale susceptibility status of Ae. aegypti [8, 13, 18], while some field release of Wolbachia-infected Ae. aegypti are essen- have already opted for the newly revised guideline tial before this approach would show success in dengue [97, 99]. In recent times, WHO has released the latest control programmes throughout dengue-endemic version of test procedures to detect insecticide resistance countries. for both Aedes larvae and adults [144]. All researchers It is irrefutable that chemical insecticides remain the are recommended to adhere to the changes made by primary vector-control intervention, specifically during WHO on the guidelines to evaluate the resistance status an emergency epidemic. When Ae. aegypti exhibited a of field Aedes population. Furthermore, future studies propensity to develop resistance to countless groups of should pinpoint on widening the number of sampling chemical insecticides leading to loss of functions, insect sites on a wide array of active ingredients of the pyreth- growth regulators (IGRs) may likely reduce resistance roid group that are yet to be tested in most cases, developing. The discovery of IGRs is in accordance with including resmethrin, bifenthrin, flumethrin and tralo- the knowledge of their growth, development, function methrin. These may have potential in effective control of and behavior. Thus, the use of IGRs has the likelihood Ae. aegypti or cross-resistance within the active ingredi- to conquer the market of many other insecticides, and ents of the pyrethroid group that may have already oc- Lau et al. [141] reported that this group of insecticides curred whereby the last resort would be abandoning of poses encouraging results to control the field popula- the pyrethroid group of insecticides. The prevalent use tions of Ae. aegypti, specifically cyromazine. of pyrethroid-based mosquito coils calls for further val- Pyrethroid resistance in Southeast Asian Ae. aegypti idation on their efficacies across Southeast Asia. As of should not be overlooked. Many countries rely on the now, little has been reported on the efficacies of these interventions of chemical insecticides to control the mosquito coils to Ae. aegypti populations. mosquito vectors of dengue. In this review of literature, Efforts of understanding the aforementioned mecha- several issues that highlight the need for immediate at- nisms on Ae. aegypti are urgently required, especially in tention are addressed. Undeniably, these studies demon- some dengue-endemic countries with unavailability of strated a strong tendency of lopsided geographical associated reports, as vector control against Ae. aegypti Amelia-Yap et al. Parasites & Vectors (2018) 11:332 Page 13 of 17 continues to be the corner stone in preventing dengue S-transferases; IGR: Insect growth regulator; kdr: Knockdown resistance; PBO: Piperonyl butoxide; PCR: Polymerase chain reaction; SNP: Single transmission and outbreak control. Bioassays are only nucleotide polymorphism; Vssc: Voltage-sensitive sodium channel; capable in detecting resistance that has already existed WHO: World Health Organization in a strain, while diagnostic assays can detect resistance Author details once it appears that this may avoid the failure in vector Tropical Infectious Diseases Research & Education Centre (TIDREC), management. Kdr assays have long been used for detect- 2 University of Malaya, 50603 Kuala Lumpur, Malaysia. Institute of Biological ing point mutations to observe the effect of control tac- Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia. tics on insecticide resistance, but it is crucial to note that these molecular assays of target site resistance Funding should also not replace bioassays until other resistance This study was funded by University of Malaya research grant (RP021D- 16SUS). mechanisms, e.g. metabolic resistance can be comple- mented by comparable assays. A major advantage of the Authors’ contributions molecular approach is that sequencing of Ae. aegypti CDC, MSA and VLL conceived the study. ZHAY conducted the review and drafted the manuscript. ZHAY and VLL wrote the final version of the genome aids in progressive study on insecticide resist- manuscript. All authors read and approved the final manuscript. ance mechanisms and further research should focus on searching for new diagnostic markers of pyrethroid Ethics approval and consent to participate Not applicable. resistance in dengue vectors. Biochemical assays in de- tecting enzymes linked to pyrethroid resistance have Competing interests been utilized in several Southeast Asian countries, be- The authors declare that they have no competing interests. cause these assays deliver important information for esti- mating resistance. However, the short of specificity and Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in sensitivity of some assays may lead to complications in published maps and institutional affiliations. analyzing data. As for the addition of synergists, such as PBO used to examine the significant of metabolic resist- Author details Tropical Infectious Diseases Research & Education Centre (TIDREC), ance, the protocol can be very problematic as a huge University of Malaya, 50603 Kuala Lumpur, Malaysia. Institute of Biological amount of alive Ae. aegypti populations will be needed. Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Hence, the above-mentioned challenge in biochemical Malaysia. assays are more difficult when analyzing the use of syn- Received: 7 March 2018 Accepted: 14 May 2018 ergist data. References Conclusions 1. World Health Organization. Dengue and severe dengue. 2017. http://www. 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