Unforeseen pathologies caused by malaria

Unforeseen pathologies caused by malaria Abstract Individuals from malaria-endemic regions often acquire partial immunity after multiple repeated infections throughout their lives. This partial immunity prevents them from developing severe complications and they often remain asymptomatic with a persistent, low parasite density in the blood, and therefore the necessity for treatment is neglected. These patients with chronic, asymptomatic malaria serve as a reservoir for Plasmodium parasite transmission, becoming a major obstacle for eradication efforts. The constant exposure to malaria infection may have benefits in the short term by conferring protection from acute, severe malaria; however, it may cause substantially more harm in the long term. Rather than the parasite burden itself, the complications induced by the dysregulated immune responses and the tissue damage done by the parasites and their products can cause chronic and irreversible suffering. Furthermore, the complete clearance of parasites in the body may not lead to complete recovery from the disease as complications can still persist. The fact that there are chronic pathologies caused by malaria that mostly remain obscure and have the potential to cause a serious burden has recently been gaining attention. Here, we present and discuss the evidence of unforeseen pathologies and the risks associated with malaria. bone marrow, chronic inflammation, genomic instability, malaria, osteoblast and osteoclast Introduction Annually there are more than 200 million cases of malaria infection in humans worldwide. Although the mortality rate has reduced to less than 500 thousand cases (1), millions of malaria survivors may still be suffering from malaria-related complications. The five species of Plasmodium parasites that cause malaria in humans are P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi, each with varying virulence and antigenic variation. The Plasmodium parasites take advantage of the host for survival and have evolved to acquire strategies to escape from the host immune attack to ensure successive transmission (2). Plasmodium parasites require the invertebrate mosquito host and the vertebrate host to complete the complex parasite life cycle. When the parasites in the form of sporozoites are injected into the skin of the human host during a mosquito blood meal, most of them travel to the liver. The traversal of the skin by sporozoites and the subsequent infection in the liver do not cause clinical symptoms, although host immune responses are initiated (3, 4). Most of the sporozoites differentiate into hepatocytic merozoites, although P. vivax also forms dormant hypnozoites in the liver that can be activated to cause relapse upon triggering (5). The merozoites enter the bloodstream upon hepatocyte rupture to infect erythrocytes. As a strategy for parasite survival, the parasites cause erythrocyte membrane modification and digest the host hemoglobin for nutrient source (6). The heme released from hemoglobin digestion is quickly biocrystallized by the parasite into hemozoin to avoid heme-mediated toxicity. The resultant hemozoin is non-toxic to the parasite but exhibits various immune-modulatory effects on the host (7, 8). The synchronized rupture of mature, infected red blood cells (iRBC) in the schizont stage causes rhythmic chills and fever, and subsequent erythrocytic infection and hemolysis lead to jaundice and anemia. Malaria infection causes mild to severe symptoms, depending on both parasite and host factors. Uncomplicated malaria infection is usually accompanied by acute symptoms like recurrent fever, nausea, headache, diarrhea, body aches, joint pain and fatigue. In severe malaria cases, the infection can cause respiratory distress, kidney failure, metabolic acidosis, severe anemia and cerebral malaria (CM). CM is the most severe complication, which leads to coma and death due to cerebral hemorrhage and edema caused by blood–brain barrier (BBB) disruption (9, 10). Survival of malaria patients is the upmost concern in the endemic regions, where the focus of treatment is put on rescuing the patients from severe malaria to reduce mortality. The chronic outcome of repeated infections, relapse and untreated chronic, asymptomatic malaria are often neglected (11). Some symptoms may not prevail immediately after recovery from infection but the persisting damage caused by malaria may be evident later in life or upon triggering by other factors (Fig. 1). In this Special Issue article, we would like to concentrate on the ‘unforeseen’ complications caused by malaria, rather than the deadly complications. Fig. 1. View largeDownload slide The unforeseen potential of malaria to cause various chronic complications. Malaria may induce reversible or permanent damage to the central nervous system that leads to neurological sequelae. Dysregulation of host immunity during malaria infection may alter vaccine responses, increase susceptibility to other infections, enhance disruption of uninfected erythrocytes and increase the tendency of chromosomal damage. Malaria may also cause tissue pathology within the gastrointestinal tract and the bone. Fig. 1. View largeDownload slide The unforeseen potential of malaria to cause various chronic complications. Malaria may induce reversible or permanent damage to the central nervous system that leads to neurological sequelae. Dysregulation of host immunity during malaria infection may alter vaccine responses, increase susceptibility to other infections, enhance disruption of uninfected erythrocytes and increase the tendency of chromosomal damage. Malaria may also cause tissue pathology within the gastrointestinal tract and the bone. Neurological sequelae: common or unforeseen complication? Neurological sequelae are generally considered as a common consequence of CM that can persist for years in children after recovery from P. falciparum infection (12). Recent evidence, however, suggests that CM is not the only cause of neurological impairment as it has also been noticed in children infected with less-virulent Plasmodium species or with uncomplicated malaria (13–15). Moreover, the presence of neurological damage in murine malaria models after recovery from a single Plasmodium infection in the absence of BBB breakage indicates that the persistent neurological damage could happen without CM and regardless of early anti-malarial treatment (16, 17). Clearly, there are complex and unforeseen effects of malaria infection on the brain. Some characteristics of neurological sequelae after CM include reversible blindness, long-lasting loss of speech, hearing defects, epilepsy, cognitive impairment, behavioral changes and impaired motor function and mobility (18–20). However, the early signs of neurological impairment may not always be apparent right after recovery from severe malaria; the symptoms may only begin to prevail in later years when more advanced cognitive ability is required to solve complex tasks (21–23). Serious problems can arise with the survivor’s mental and physical abilities in the long term if any neurological deficit is left unattended in children (24). An inability to carry out daily activities independently and poor performance in school and work later in life can impose a social and economic burden to the community. The mechanisms of neurological sequelae are not well understood although several possibilities and causal factors have been postulated (25). Malaria-induced neurological damage could be a consequence of focal hypoxic or ischemic injury caused by microvascular obstruction and inflammation in the brain. Temporary cerebral vessel occlusion has been shown to rapidly induce platelet and fibrin deposition within the cerebral vessel that prolong blood flow obstruction, leading to activation of microglia with increased inflammatory responses and oxidative stress that eventually causes myelin degeneration, neuronal synapse loss and cell death at the site of the occlusion (26, 27). The cell death caused by ischemic injury mainly resembles autophagy, with increased numbers of dense punctate dots containing microtubule-associated protein light chain 3 (LC3) detected in the neuron clusters and epithelial cells, with a lower extent of apoptotic cell death (26). Moreover, small intracerebral hemorrhages were still apparent in mice that recovered from CM after anti-malarial treatment (28), suggesting that microglia may continue to be activated to inflict continuous neuronal injury after recovery from CM (29). The effect of vessel occlusion on neuronal damage was confirmed in CM patients, with a correlation of axonal and myelin damage with vessel occlusion in the brain (30). Malaria-induced neurological damage may also involve other factors such as elevated auto-antibodies against neuronal dendrites and increased excitotoxic kynurenine and quinolinic acid in the cerebrospinal fluid, which have been detected in malaria patients, being especially higher in those with CM (31, 32). Cognitive impairment and behavioral changes after survival from CM might be partially attributable to the deterioration of senses such as smell, vision and hearing. The dense microvasculature surrounded by astrocytes in the olfactory bulb, which senses smell, serves as the most vulnerable site of damage during the initiation of experimental CM (9). Sequestration of iRBC in the olfactory capillaries causes the disruption of epithelium tight junction and endothelium activation, leading to the secretion of CCL21 from activated astrocytes that recruits pathological CXCR3+CD8+ T cells to cause bleeding in the olfactory bulb. Although early treatment may prevent death from CM, olfactory dysfunction causes the loss of smell function and might have an impact on perception, memory and behavior especially in children during the learning process (33). Hearing impairment is a common consequence experienced by malaria patients that may affect attention and speech learning (34). Although anti-malarial drugs like chloroquine, mefloquine and quinine have ototoxicity and visual side effects (35–37), artemisinin-based combination therapy has been reported to reverse the hearing impairment caused by uncomplicated malaria and severe malaria (38, 39), indicating that malaria may cause direct damage to the inner ear. Schmutzhard et al. have demonstrated in several studies in mice that the cochlear damage is evident in both CM and non-CM models (40, 41). The expression of ICAM1 on the endothelium of stria vascularis in the cochlea (40) and the apoptosis of spiral ganglion neurons, limbus and mostly fibrocytes in the spiral ligament adjacent to the stria vascularis were correlated with malaria severity and hearing impairment (41). Similar to the BBB breakage in brain, disruption of the blood–labyrinth barrier in the inner ear also occurs in mice that succumbed to CM (41). Although these studies showed pathology in the cochlea and olfactory only during the acute phase and did not further evaluate whether the defect is reversible upon recovery from malaria, nevertheless, individuals with chronic, asymptomatic malaria and those who are repeatedly infected with malaria may have a higher risk of developing gradual hearing impairment or distorted odor perception. Still there is a lack of biological markers to identify the individuals at risk of neurological sequelae soon after recovery from malaria. Being aware of the possible neurological consequences following recovery from malaria can help early diagnosis, treatment and rehabilitation before the complications worsen. Malaria as a cause of genomic instability It is known that constant and long-term exposure to malaria infection is required for antibody-mediated protection. However, in reality, patients with chronic malaria generally develop adaptive immune responses that give rise to short-lived and low-affinity antibodies (42). Why and how this occurs is not completely understood. One of the possibilities is that P. falciparum infection drives Th1 responses that dampen adaptive immunity by promoting the differentiation of the less functional CXCR3+ Th1-polarized T follicular helper (Tfh1) cells and the expansion of exhausted, atypical CD21–CD27– memory B cells with impaired proliferation and BCR signaling, which mainly give rise to IgG3 antibody production (43, 44). Although IgG3 is potent in conferring protection against invasion of erythrocytes by merozoites, the short half-life of IgG3 (6.1 days during malaria compared with the usual 7.0-day half-life) and the low level of IgG1 with a reduced half-life (9.8 days during malaria compared with the usual 21.0-day half-life) are only able to promote partial immunity for asymptomatic malaria with constant low parasitemia (44, 45). Importantly, the constant exposure to malaria antigens because of incomplete parasite clearance continuously activates germinal center (GC) B cells to undergo somatic hypermutation and class-switch recombination—both mediated through activation-induced cytidine deaminase (AID)—over an extended period of time (46). Overexpression of AID may also increase DNA instability by inducing non-specific DNA breakage at off-target sites including the oncogene c-myc to promote chromosome translocation, which has been shown to increase the risk of lymphomagenesis with the tendency to give rise to a mature B-cell lymphoma phenotype. Interestingly, chromosomal translocation was also found to be widespread in malaria-induced GC B cells regardless of AID (46), suggesting that the genomic instability may not be confined only to the GC compartment. Supporting this, malaria patients were recently found to have shortened telomeres following a single acute infection and this phenomenon was also detected in multiple organs (liver, lungs, spleen, heart, kidney and brain) in an avian malaria model in which it correlates with reduced lifespan of the birds (47, 48). The shortening of telomeres may lead to accelerated cell senescence, aging and organ dysfunction in populations repeatedly exposed to malaria infections, implying the potential chronic outcomes caused by acute malaria infection. Furthermore, there is an interesting overlapping endemicity and a close correlation between malaria and endemic Burkitt’s lymphoma (eBL), a lymphoma known to originate from GC B cells. Burkitt’s lymphoma involves a reciprocal chromosomal translocation of the oncogene c-myc and the immunoglobulin gene locus in GC B cells. Many studies showed that malaria increases the infection frequency of EBV and that the number of cases of eBL declined following malaria eradication (49). Although almost all cases of eBL that occur in malaria-holoendemic regions are positive for EBV infection, Burkitt’s lymphoma can occur without EBV infection in non-endemic regions, and EBV infection alone does not usually cause the development of Burkitt’s lymphoma outside of the endemic regions. The relationship between malaria and EBV infection and their roles in eBL development are still unclear. However, several lines of evidence suggest that malaria is the driving force for eBL development. Although the genetic pressure exerted by malaria alone is insufficient to induce eBL, malaria may act synergistically with EBV infection to increase the frequency of DNA damage to trigger tumorigenesis. The expansion of GC B cells in response to malaria infection profoundly increases the pool of cells available for latent infection by EBV. The infected GC B cells differentiate into terminally differentiated plasma cells and memory cells during malaria infection. Differentiation of plasma cells initiates the viral lytic phase to produce more virus to infect the expanded population of GC B cells (50), while the infected memory B cells remain in the latent state; however, they can be re-activated by the Plasmodium membrane protein cysteine-rich inter-domain region 1α (CIDR1α) to transform into the replicative lytic phase (51). Another piece of evidence supporting the role of malaria in eBL development is the ability of the Plasmodium crude extract to suppress EBV lytic-gene expression—possibly via TLR9 expressed on B cells—thus inhibiting the lysis of EBV-infected cells while maintaining EBV in the latent state (52), where the cells are highly prone to chromosomal damage and malignant transformation. The long-term persistence of Plasmodium products including hemozoin in the lymphoid tissues may consistently modulate the host immune responses exploited by EBV, suggesting that the impact of malaria on eBL is not limited to during acute malaria infection. Although several latent EBV proteins have been identified as oncogenic proteins that promote genomic instability in infected B cells (53, 54), these proteins are only able to induce lymphoma development in immunocompromised hosts in the absence of T cells because otherwise there is rapid killing of the tumor cells by CD8+ T cells (55). As malaria has been shown to suppress the EBV-specific T-cell immunity in humans that correlates with the higher viral load (56), this may explain why eBL is more prevalent in malaria-endemic regions; and EBV infection alone does not spontaneously induce lymphomagenesis in immunocompetent hosts. Overall these studies suggest that EBV may take advantage of malaria infection to exacerbate genetic instability. Chronic malaria infection, repeated infections and other co-infections in the region might cumulatively contribute to the chronic antigenic stimulation and immune dysregulation. The influence of malaria on susceptibility to other infections Epidemiological and experimental evidence suggests that malaria may be an indirect risk factor contributing to susceptibility to and complications of other diseases (57). Bacterial infections such as salmonellosis and tuberculosis, as well as helminth and HIV infections, are fairly common in malaria-endemic regions. It is surprising not only that anti-malaria intervention reduces malaria-specific mortality but also that all-cause morbidity and overall mortality decline, suggesting that malaria exerts pressure on other diseases (58). It is possible that malaria infection may cause pathological damage to the lymphoid organs such as spleen, leading to alterations in immune cell populations and dysregulation of immune responses that render the host vulnerable to other infections as well as altering responses to vaccines (59, 60). The acute and chronic phases of malaria infection dynamically regulate the distribution and responsiveness of innate and adaptive immune cells. The responses to secondary infections and vaccinations have been suggested to be partly affected by the skewing of the Th1/Th2 balance during the course of infection; thus the timing of the acquisition of the secondary infection, relative to malaria, may differentially affect the outcome of the secondary disease or vaccination (61). In the case of malaria, recent studies have revealed the complexity of the immune regulation, which involves the dysregulation of cytokine expression and the expansion of immune-suppressive subsets such as Tr1 (Foxp3– type 1 regulatory T) cells, Tr27 (IL-27-producing Foxp3– regulatory T) cells, Tfh1 cells and atypical memory B cells (43, 44, 62, 63). The immune dysregulation during malaria infection has been shown to involve the inhibition of Th1 cell development but rather promotes the differentiation of Tr1 cells that co-secrete IL-10 and IFN-γ (also known as type 2 interferon, IFN-2) and suppress effector T-cell responses and dampen humoral immunity (62). These responses were found to be mediated by several factors such as type 1 interferon (IFN-1) produced by plasmacytoid dendritic cells (64), and IL-27 mainly produced by the newly defined Tr27 cells (63, 65). The high IL-10 production from Tr1 cells may counteract the IFN-γ activity by inhibiting macrophage cytokine production and anti-microbicidal activity (Fig. 2). Fig. 2. View largeDownload slide Immune dysregulation during malaria infection increases the susceptibility to secondary infections. Malaria infection inhibits Th1 cell differentiation and expands Tr1 cells via IL-27 from malaria-specific Tr27 cells and IFN-1 from dendritic cells. Tr1 cells co-express a high level of IL-10 and IFN-γ that suppresses the differentiation of the CXCR3− Tfh cells which act as efficient B-cell helpers, while inducing the differentiation of the less efficient CXCR3+ Tfh1 cells. The expansion of Tbet+ atypical B cells mediated by IFN-γ impairs BCR signaling and reduces the effector function. The high IL-10 production during malaria infection also inhibits macrophage responsiveness to IFN-γ and suppresses the microbicidal activity of macrophages to control bacterial growth. Malaria infection causes dysbiosis in the gut to increase the susceptibility to secondary infection. Sequestration of iRBC causes capillary breakage in the villi that drives the infiltration and activation of lymphocytes, neutrophils and mast cells to induce inflammation and disrupt the epithelial tight junctions. The epithelial damage increases the intestinal permeability that allows the invasion of bacteria from the gut. Fig. 2. View largeDownload slide Immune dysregulation during malaria infection increases the susceptibility to secondary infections. Malaria infection inhibits Th1 cell differentiation and expands Tr1 cells via IL-27 from malaria-specific Tr27 cells and IFN-1 from dendritic cells. Tr1 cells co-express a high level of IL-10 and IFN-γ that suppresses the differentiation of the CXCR3− Tfh cells which act as efficient B-cell helpers, while inducing the differentiation of the less efficient CXCR3+ Tfh1 cells. The expansion of Tbet+ atypical B cells mediated by IFN-γ impairs BCR signaling and reduces the effector function. The high IL-10 production during malaria infection also inhibits macrophage responsiveness to IFN-γ and suppresses the microbicidal activity of macrophages to control bacterial growth. Malaria infection causes dysbiosis in the gut to increase the susceptibility to secondary infection. Sequestration of iRBC causes capillary breakage in the villi that drives the infiltration and activation of lymphocytes, neutrophils and mast cells to induce inflammation and disrupt the epithelial tight junctions. The epithelial damage increases the intestinal permeability that allows the invasion of bacteria from the gut. Consistent with the findings in malaria, recently a study on Mycobacterium tuberculosis showed similar activation of a subset of T cells that co-express IFN-γ and IL-10 during the chronic phase after day 21 post-infection, but not during the acute phase, and it was also partially dependent on both IFN-1 and IL-27 (67–69). Additionally, Plasmodium infection in mice suffering from chronic tuberculosis was shown to further dampen the immune responses against mycobacteria by enhancing IL-10 production in macrophages and T cells and inhibiting IFN-γ-mediated macrophage activation and nitric oxide production (69). Besides its effects on macrophages, chronic malaria may also affect neutrophil function as reduced neutrophil oxidative burst was observed among Gambian children with uncomplicated malaria (70). Mature neutrophils are an important anti-Plasmodium component of the host (71), but the induction of heme oxygenase-1 during malarial hemolysis increases the mobilization of immature neutrophils from the bone marrow that lack oxidative burst to kill the phagocytosed bacteria (72). However, the role of malaria is not solely on hemolytic anemia, as a mouse malaria model showed that hemolytic anemia only partially contributes to this susceptibility by suppressing macrophage microbicidal activity, while Plasmodium-specific factors play a more significant role by inducing IL-10 and down-regulating IL-12p70, which cause the impaired control of bacterial infection in gut mucosa (73–75). The gut serves as a vulnerable site for bacteria invasion during malaria. Malaria patients were commonly found to have mucosal edema and congestion accompanied by superficial bleeding, microthrombosis and gastric atrophy, which cause them to suffer from gastric symptoms including epigastralgia, nausea and vomiting (76). Plasmodium parasites were found to sequester in the small capillaries in the intestinal villi in autopsies of children who died of CM (77). Intestinal malabsorption and increased gastrointestinal permeability were prevalent in severe malaria cases (78, 79). The enhanced intestinal permeability was demonstrated, in a mouse model of malaria, to be associated with increased recruitment and activation of mast cells in the ileal villi and crypts, with elevated histamine and hypoargininemia (80). This study further showed that the disruption of the intestinal barrier increased the translocation of bacteria. The pathological damage caused by malaria in the gut has recently been shown to cause dysbiosis that alters the proportions of microbiota in the intestine (81). Malaria infection can breach mucosal immunity and affect the population of microbiota and vice versa (82, 83), thereby increasing the severity of pathology and risk of other infections (Fig. 2). Malaria as a cause of growth retardation and bone problems Most of the malaria-endemic areas are in lower socio-economy conditions, in which there is a lack of adequate healthcare, proper hygiene and nutritional practice that increases the morbidity of infections. The nutritional status could play a role in controlling the disease severity and overall outcome. For instance, a very recent study showed that a high-fat diet can exert a protective effect on liver-stage malaria infection (84). The disease severity and growth retardation in malaria-endemic regions have often been associated with malnutrition, but recent observations have brought to light the direct contribution of the malaria burden on physical growth in these regions (85). Although delayed skeletal maturation and prominent bone porosity were prevalent in these regions, it has been very difficult to determine whether malaria is the main cause of these bone defects (86, 87). A convincing study with proper control groups clearly showed that stunting and wasting were higher in children exposed to malaria compared with those protected from infection in the same community (88). Although these studies in human populations have suggested the potential suppressive effect of malaria on bone and growth development, recent mouse malaria models have confirmed the direct acute and the chronic effects of malaria infection on bone remodeling (89). This recent study showed that a single malaria infection can cause chronic bone loss long after recovery from infection (89). Accordingly, the acute and chronic phases of malaria infection have distinct mechanisms that eventually lead to the severe outcome—loss of bone. Initially, during acute malaria infection, the hemolysis and cytokine storm halted bone remodeling with inhibition of both osteoclast and osteoblast formation and activity, causing the initiation of bone loss. It is known that the absence of continuous bone replacement by bone remodeling may lead to an increase in microdamage and cracks due to mechanical stress on the bone (90). However, the chronic bone loss after recovery from malaria was found to be attributable to the continuous accumulation of Plasmodium products that elicit chronic inflammation through the activation of bone cell precursors via MyD88 signaling (89). The chronic inflammation mediates the up-regulation of the osteoclast differentiation factor, RANKL, on osteoblasts to promote osteoclast formation and hyper-activation (Fig. 3). Fig. 3. View largeDownload slide Hidden pathology of malaria within the bone. The long-term retention of Plasmodium products in the bone marrow changes the environment there. These Plasmodium products may interact directly with other bone marrow cells such as mesenchymal stromal cells and HSCs, or indirectly through cytokines to cause the alteration of bone marrow cellular composition and function. The accumulation of Plasmodium products in the bone marrow induces inflammation in osteoclast precursors, osteoblast precursors and mature osteoblasts. The inflammatory cytokines induce RANKL expression on mature osteoblasts to trigger activation of osteoclast formation which leads to an increased resorption activity and bone loss. Fig. 3. View largeDownload slide Hidden pathology of malaria within the bone. The long-term retention of Plasmodium products in the bone marrow changes the environment there. These Plasmodium products may interact directly with other bone marrow cells such as mesenchymal stromal cells and HSCs, or indirectly through cytokines to cause the alteration of bone marrow cellular composition and function. The accumulation of Plasmodium products in the bone marrow induces inflammation in osteoclast precursors, osteoblast precursors and mature osteoblasts. The inflammatory cytokines induce RANKL expression on mature osteoblasts to trigger activation of osteoclast formation which leads to an increased resorption activity and bone loss. These novel findings unveil one of the hidden pathologies within the bone tissue caused by malaria infection that raise our awareness of an unforeseen risk of bone pathology in malaria patients, especially those with chronic asymptomatic infections, repeated infections and relapses. How long the Plasmodium products remain in the bone marrow to cause tissue insult is, however, unknown as is whether their presence would affect bone marrow hematopoiesis. The underlying mechanisms of bone destruction during malaria infection could be multifactorial. Inflammation is known to contribute to hematopoietic stem cell (HSC) regulation and alter the bone marrow cellular composition (91); however, there is a lack of clear understanding of how the stress is sensed to bring about the changes in the bone marrow during malaria infection. Signals such as PAMPs or DAMPs (pathogen- or damage-associated molecular patterns) or cytokines might (1) be directly sensed by the HSC and cause a change in the transcriptome and differentiation, (2) induce apoptosis and expansion of certain progenitors or (3) change the bone marrow niche microenvironment through stromal cell alterations that indirectly influence HSC and osteogenic cells (92). Mesenchymal stromal cells constitute a large proportion in the bone marrow and play multiple roles in the regulation of bone remodeling, providing a conducive microenvironment in specific niches for blood cell production and development, and regulating the retention and mobilization of bone marrow cells. Malaria infection may affect stromal cell regulation either directly via recognition of the parasite antigen or its products, or indirectly by cytokine dysregulation that affects the osteogenic differentiation and expansion of myeloid progenitors in the bone marrow. Unlike other infectious diseases, malaria leaves its signature Plasmodium products in the bone marrow long term, even after recovery from infection, introducing foreign material into the bone marrow environment. It has been shown that osteoclasts, osteoblasts and their precursors directly respond to these Plasmodium products in the absence of on-going active infection (89). However, it remains to be explored how the other bone marrow cells interact and respond to these persistent parasite products and whether they have a role in modulating the bone marrow composition that affects hematopoiesis. Conclusions The pathology of malaria is more complex than we thought. Recent studies have revealed that there are still risks of unknown, unforeseen consequences of malaria that could link to various complications and diseases. The chronic, hidden complications might be among the obstacles for socio-economic development while hindering the malaria patients from living a normal, healthy life and to unleash their full potential for the development of their country (93). An overall health improvement may also decrease overall morbidity and mortality caused by other opportunistic diseases. Although treatments mainly focus on major complications, the possibility of chronic complications should be taken into consideration with follow-up examinations and adjunct therapies. Understanding the hidden cost of malaria can help to identify the early symptoms before the development of later complications and to determine the most suitable treatment for the disease. Conflicts of interests statement: The authors declare no competing interests. Acknowledgements These studies are supported by Grants-in-Aid for Scientific Research (KAKENHI KIBAN B grant no. 16H05181) and the Japan Agency for Medical Research and Development (AMED J-PRIDE 17fm0208021h0001). References 1 World Health Organization. 2016. World Malaria Report 2016 . World Health Organization, Geneva, Switzerland. 2 Rénia, L. and Goh, Y. S. 2016. Malaria parasites: the great escape. Front. Immunol . 7: 463. Google Scholar CrossRef Search ADS PubMed  3 Amino, R., Giovannini, D., Thiberge, S.et al.   2008. 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Unforeseen pathologies caused by malaria

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Abstract

Abstract Individuals from malaria-endemic regions often acquire partial immunity after multiple repeated infections throughout their lives. This partial immunity prevents them from developing severe complications and they often remain asymptomatic with a persistent, low parasite density in the blood, and therefore the necessity for treatment is neglected. These patients with chronic, asymptomatic malaria serve as a reservoir for Plasmodium parasite transmission, becoming a major obstacle for eradication efforts. The constant exposure to malaria infection may have benefits in the short term by conferring protection from acute, severe malaria; however, it may cause substantially more harm in the long term. Rather than the parasite burden itself, the complications induced by the dysregulated immune responses and the tissue damage done by the parasites and their products can cause chronic and irreversible suffering. Furthermore, the complete clearance of parasites in the body may not lead to complete recovery from the disease as complications can still persist. The fact that there are chronic pathologies caused by malaria that mostly remain obscure and have the potential to cause a serious burden has recently been gaining attention. Here, we present and discuss the evidence of unforeseen pathologies and the risks associated with malaria. bone marrow, chronic inflammation, genomic instability, malaria, osteoblast and osteoclast Introduction Annually there are more than 200 million cases of malaria infection in humans worldwide. Although the mortality rate has reduced to less than 500 thousand cases (1), millions of malaria survivors may still be suffering from malaria-related complications. The five species of Plasmodium parasites that cause malaria in humans are P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi, each with varying virulence and antigenic variation. The Plasmodium parasites take advantage of the host for survival and have evolved to acquire strategies to escape from the host immune attack to ensure successive transmission (2). Plasmodium parasites require the invertebrate mosquito host and the vertebrate host to complete the complex parasite life cycle. When the parasites in the form of sporozoites are injected into the skin of the human host during a mosquito blood meal, most of them travel to the liver. The traversal of the skin by sporozoites and the subsequent infection in the liver do not cause clinical symptoms, although host immune responses are initiated (3, 4). Most of the sporozoites differentiate into hepatocytic merozoites, although P. vivax also forms dormant hypnozoites in the liver that can be activated to cause relapse upon triggering (5). The merozoites enter the bloodstream upon hepatocyte rupture to infect erythrocytes. As a strategy for parasite survival, the parasites cause erythrocyte membrane modification and digest the host hemoglobin for nutrient source (6). The heme released from hemoglobin digestion is quickly biocrystallized by the parasite into hemozoin to avoid heme-mediated toxicity. The resultant hemozoin is non-toxic to the parasite but exhibits various immune-modulatory effects on the host (7, 8). The synchronized rupture of mature, infected red blood cells (iRBC) in the schizont stage causes rhythmic chills and fever, and subsequent erythrocytic infection and hemolysis lead to jaundice and anemia. Malaria infection causes mild to severe symptoms, depending on both parasite and host factors. Uncomplicated malaria infection is usually accompanied by acute symptoms like recurrent fever, nausea, headache, diarrhea, body aches, joint pain and fatigue. In severe malaria cases, the infection can cause respiratory distress, kidney failure, metabolic acidosis, severe anemia and cerebral malaria (CM). CM is the most severe complication, which leads to coma and death due to cerebral hemorrhage and edema caused by blood–brain barrier (BBB) disruption (9, 10). Survival of malaria patients is the upmost concern in the endemic regions, where the focus of treatment is put on rescuing the patients from severe malaria to reduce mortality. The chronic outcome of repeated infections, relapse and untreated chronic, asymptomatic malaria are often neglected (11). Some symptoms may not prevail immediately after recovery from infection but the persisting damage caused by malaria may be evident later in life or upon triggering by other factors (Fig. 1). In this Special Issue article, we would like to concentrate on the ‘unforeseen’ complications caused by malaria, rather than the deadly complications. Fig. 1. View largeDownload slide The unforeseen potential of malaria to cause various chronic complications. Malaria may induce reversible or permanent damage to the central nervous system that leads to neurological sequelae. Dysregulation of host immunity during malaria infection may alter vaccine responses, increase susceptibility to other infections, enhance disruption of uninfected erythrocytes and increase the tendency of chromosomal damage. Malaria may also cause tissue pathology within the gastrointestinal tract and the bone. Fig. 1. View largeDownload slide The unforeseen potential of malaria to cause various chronic complications. Malaria may induce reversible or permanent damage to the central nervous system that leads to neurological sequelae. Dysregulation of host immunity during malaria infection may alter vaccine responses, increase susceptibility to other infections, enhance disruption of uninfected erythrocytes and increase the tendency of chromosomal damage. Malaria may also cause tissue pathology within the gastrointestinal tract and the bone. Neurological sequelae: common or unforeseen complication? Neurological sequelae are generally considered as a common consequence of CM that can persist for years in children after recovery from P. falciparum infection (12). Recent evidence, however, suggests that CM is not the only cause of neurological impairment as it has also been noticed in children infected with less-virulent Plasmodium species or with uncomplicated malaria (13–15). Moreover, the presence of neurological damage in murine malaria models after recovery from a single Plasmodium infection in the absence of BBB breakage indicates that the persistent neurological damage could happen without CM and regardless of early anti-malarial treatment (16, 17). Clearly, there are complex and unforeseen effects of malaria infection on the brain. Some characteristics of neurological sequelae after CM include reversible blindness, long-lasting loss of speech, hearing defects, epilepsy, cognitive impairment, behavioral changes and impaired motor function and mobility (18–20). However, the early signs of neurological impairment may not always be apparent right after recovery from severe malaria; the symptoms may only begin to prevail in later years when more advanced cognitive ability is required to solve complex tasks (21–23). Serious problems can arise with the survivor’s mental and physical abilities in the long term if any neurological deficit is left unattended in children (24). An inability to carry out daily activities independently and poor performance in school and work later in life can impose a social and economic burden to the community. The mechanisms of neurological sequelae are not well understood although several possibilities and causal factors have been postulated (25). Malaria-induced neurological damage could be a consequence of focal hypoxic or ischemic injury caused by microvascular obstruction and inflammation in the brain. Temporary cerebral vessel occlusion has been shown to rapidly induce platelet and fibrin deposition within the cerebral vessel that prolong blood flow obstruction, leading to activation of microglia with increased inflammatory responses and oxidative stress that eventually causes myelin degeneration, neuronal synapse loss and cell death at the site of the occlusion (26, 27). The cell death caused by ischemic injury mainly resembles autophagy, with increased numbers of dense punctate dots containing microtubule-associated protein light chain 3 (LC3) detected in the neuron clusters and epithelial cells, with a lower extent of apoptotic cell death (26). Moreover, small intracerebral hemorrhages were still apparent in mice that recovered from CM after anti-malarial treatment (28), suggesting that microglia may continue to be activated to inflict continuous neuronal injury after recovery from CM (29). The effect of vessel occlusion on neuronal damage was confirmed in CM patients, with a correlation of axonal and myelin damage with vessel occlusion in the brain (30). Malaria-induced neurological damage may also involve other factors such as elevated auto-antibodies against neuronal dendrites and increased excitotoxic kynurenine and quinolinic acid in the cerebrospinal fluid, which have been detected in malaria patients, being especially higher in those with CM (31, 32). Cognitive impairment and behavioral changes after survival from CM might be partially attributable to the deterioration of senses such as smell, vision and hearing. The dense microvasculature surrounded by astrocytes in the olfactory bulb, which senses smell, serves as the most vulnerable site of damage during the initiation of experimental CM (9). Sequestration of iRBC in the olfactory capillaries causes the disruption of epithelium tight junction and endothelium activation, leading to the secretion of CCL21 from activated astrocytes that recruits pathological CXCR3+CD8+ T cells to cause bleeding in the olfactory bulb. Although early treatment may prevent death from CM, olfactory dysfunction causes the loss of smell function and might have an impact on perception, memory and behavior especially in children during the learning process (33). Hearing impairment is a common consequence experienced by malaria patients that may affect attention and speech learning (34). Although anti-malarial drugs like chloroquine, mefloquine and quinine have ototoxicity and visual side effects (35–37), artemisinin-based combination therapy has been reported to reverse the hearing impairment caused by uncomplicated malaria and severe malaria (38, 39), indicating that malaria may cause direct damage to the inner ear. Schmutzhard et al. have demonstrated in several studies in mice that the cochlear damage is evident in both CM and non-CM models (40, 41). The expression of ICAM1 on the endothelium of stria vascularis in the cochlea (40) and the apoptosis of spiral ganglion neurons, limbus and mostly fibrocytes in the spiral ligament adjacent to the stria vascularis were correlated with malaria severity and hearing impairment (41). Similar to the BBB breakage in brain, disruption of the blood–labyrinth barrier in the inner ear also occurs in mice that succumbed to CM (41). Although these studies showed pathology in the cochlea and olfactory only during the acute phase and did not further evaluate whether the defect is reversible upon recovery from malaria, nevertheless, individuals with chronic, asymptomatic malaria and those who are repeatedly infected with malaria may have a higher risk of developing gradual hearing impairment or distorted odor perception. Still there is a lack of biological markers to identify the individuals at risk of neurological sequelae soon after recovery from malaria. Being aware of the possible neurological consequences following recovery from malaria can help early diagnosis, treatment and rehabilitation before the complications worsen. Malaria as a cause of genomic instability It is known that constant and long-term exposure to malaria infection is required for antibody-mediated protection. However, in reality, patients with chronic malaria generally develop adaptive immune responses that give rise to short-lived and low-affinity antibodies (42). Why and how this occurs is not completely understood. One of the possibilities is that P. falciparum infection drives Th1 responses that dampen adaptive immunity by promoting the differentiation of the less functional CXCR3+ Th1-polarized T follicular helper (Tfh1) cells and the expansion of exhausted, atypical CD21–CD27– memory B cells with impaired proliferation and BCR signaling, which mainly give rise to IgG3 antibody production (43, 44). Although IgG3 is potent in conferring protection against invasion of erythrocytes by merozoites, the short half-life of IgG3 (6.1 days during malaria compared with the usual 7.0-day half-life) and the low level of IgG1 with a reduced half-life (9.8 days during malaria compared with the usual 21.0-day half-life) are only able to promote partial immunity for asymptomatic malaria with constant low parasitemia (44, 45). Importantly, the constant exposure to malaria antigens because of incomplete parasite clearance continuously activates germinal center (GC) B cells to undergo somatic hypermutation and class-switch recombination—both mediated through activation-induced cytidine deaminase (AID)—over an extended period of time (46). Overexpression of AID may also increase DNA instability by inducing non-specific DNA breakage at off-target sites including the oncogene c-myc to promote chromosome translocation, which has been shown to increase the risk of lymphomagenesis with the tendency to give rise to a mature B-cell lymphoma phenotype. Interestingly, chromosomal translocation was also found to be widespread in malaria-induced GC B cells regardless of AID (46), suggesting that the genomic instability may not be confined only to the GC compartment. Supporting this, malaria patients were recently found to have shortened telomeres following a single acute infection and this phenomenon was also detected in multiple organs (liver, lungs, spleen, heart, kidney and brain) in an avian malaria model in which it correlates with reduced lifespan of the birds (47, 48). The shortening of telomeres may lead to accelerated cell senescence, aging and organ dysfunction in populations repeatedly exposed to malaria infections, implying the potential chronic outcomes caused by acute malaria infection. Furthermore, there is an interesting overlapping endemicity and a close correlation between malaria and endemic Burkitt’s lymphoma (eBL), a lymphoma known to originate from GC B cells. Burkitt’s lymphoma involves a reciprocal chromosomal translocation of the oncogene c-myc and the immunoglobulin gene locus in GC B cells. Many studies showed that malaria increases the infection frequency of EBV and that the number of cases of eBL declined following malaria eradication (49). Although almost all cases of eBL that occur in malaria-holoendemic regions are positive for EBV infection, Burkitt’s lymphoma can occur without EBV infection in non-endemic regions, and EBV infection alone does not usually cause the development of Burkitt’s lymphoma outside of the endemic regions. The relationship between malaria and EBV infection and their roles in eBL development are still unclear. However, several lines of evidence suggest that malaria is the driving force for eBL development. Although the genetic pressure exerted by malaria alone is insufficient to induce eBL, malaria may act synergistically with EBV infection to increase the frequency of DNA damage to trigger tumorigenesis. The expansion of GC B cells in response to malaria infection profoundly increases the pool of cells available for latent infection by EBV. The infected GC B cells differentiate into terminally differentiated plasma cells and memory cells during malaria infection. Differentiation of plasma cells initiates the viral lytic phase to produce more virus to infect the expanded population of GC B cells (50), while the infected memory B cells remain in the latent state; however, they can be re-activated by the Plasmodium membrane protein cysteine-rich inter-domain region 1α (CIDR1α) to transform into the replicative lytic phase (51). Another piece of evidence supporting the role of malaria in eBL development is the ability of the Plasmodium crude extract to suppress EBV lytic-gene expression—possibly via TLR9 expressed on B cells—thus inhibiting the lysis of EBV-infected cells while maintaining EBV in the latent state (52), where the cells are highly prone to chromosomal damage and malignant transformation. The long-term persistence of Plasmodium products including hemozoin in the lymphoid tissues may consistently modulate the host immune responses exploited by EBV, suggesting that the impact of malaria on eBL is not limited to during acute malaria infection. Although several latent EBV proteins have been identified as oncogenic proteins that promote genomic instability in infected B cells (53, 54), these proteins are only able to induce lymphoma development in immunocompromised hosts in the absence of T cells because otherwise there is rapid killing of the tumor cells by CD8+ T cells (55). As malaria has been shown to suppress the EBV-specific T-cell immunity in humans that correlates with the higher viral load (56), this may explain why eBL is more prevalent in malaria-endemic regions; and EBV infection alone does not spontaneously induce lymphomagenesis in immunocompetent hosts. Overall these studies suggest that EBV may take advantage of malaria infection to exacerbate genetic instability. Chronic malaria infection, repeated infections and other co-infections in the region might cumulatively contribute to the chronic antigenic stimulation and immune dysregulation. The influence of malaria on susceptibility to other infections Epidemiological and experimental evidence suggests that malaria may be an indirect risk factor contributing to susceptibility to and complications of other diseases (57). Bacterial infections such as salmonellosis and tuberculosis, as well as helminth and HIV infections, are fairly common in malaria-endemic regions. It is surprising not only that anti-malaria intervention reduces malaria-specific mortality but also that all-cause morbidity and overall mortality decline, suggesting that malaria exerts pressure on other diseases (58). It is possible that malaria infection may cause pathological damage to the lymphoid organs such as spleen, leading to alterations in immune cell populations and dysregulation of immune responses that render the host vulnerable to other infections as well as altering responses to vaccines (59, 60). The acute and chronic phases of malaria infection dynamically regulate the distribution and responsiveness of innate and adaptive immune cells. The responses to secondary infections and vaccinations have been suggested to be partly affected by the skewing of the Th1/Th2 balance during the course of infection; thus the timing of the acquisition of the secondary infection, relative to malaria, may differentially affect the outcome of the secondary disease or vaccination (61). In the case of malaria, recent studies have revealed the complexity of the immune regulation, which involves the dysregulation of cytokine expression and the expansion of immune-suppressive subsets such as Tr1 (Foxp3– type 1 regulatory T) cells, Tr27 (IL-27-producing Foxp3– regulatory T) cells, Tfh1 cells and atypical memory B cells (43, 44, 62, 63). The immune dysregulation during malaria infection has been shown to involve the inhibition of Th1 cell development but rather promotes the differentiation of Tr1 cells that co-secrete IL-10 and IFN-γ (also known as type 2 interferon, IFN-2) and suppress effector T-cell responses and dampen humoral immunity (62). These responses were found to be mediated by several factors such as type 1 interferon (IFN-1) produced by plasmacytoid dendritic cells (64), and IL-27 mainly produced by the newly defined Tr27 cells (63, 65). The high IL-10 production from Tr1 cells may counteract the IFN-γ activity by inhibiting macrophage cytokine production and anti-microbicidal activity (Fig. 2). Fig. 2. View largeDownload slide Immune dysregulation during malaria infection increases the susceptibility to secondary infections. Malaria infection inhibits Th1 cell differentiation and expands Tr1 cells via IL-27 from malaria-specific Tr27 cells and IFN-1 from dendritic cells. Tr1 cells co-express a high level of IL-10 and IFN-γ that suppresses the differentiation of the CXCR3− Tfh cells which act as efficient B-cell helpers, while inducing the differentiation of the less efficient CXCR3+ Tfh1 cells. The expansion of Tbet+ atypical B cells mediated by IFN-γ impairs BCR signaling and reduces the effector function. The high IL-10 production during malaria infection also inhibits macrophage responsiveness to IFN-γ and suppresses the microbicidal activity of macrophages to control bacterial growth. Malaria infection causes dysbiosis in the gut to increase the susceptibility to secondary infection. Sequestration of iRBC causes capillary breakage in the villi that drives the infiltration and activation of lymphocytes, neutrophils and mast cells to induce inflammation and disrupt the epithelial tight junctions. The epithelial damage increases the intestinal permeability that allows the invasion of bacteria from the gut. Fig. 2. View largeDownload slide Immune dysregulation during malaria infection increases the susceptibility to secondary infections. Malaria infection inhibits Th1 cell differentiation and expands Tr1 cells via IL-27 from malaria-specific Tr27 cells and IFN-1 from dendritic cells. Tr1 cells co-express a high level of IL-10 and IFN-γ that suppresses the differentiation of the CXCR3− Tfh cells which act as efficient B-cell helpers, while inducing the differentiation of the less efficient CXCR3+ Tfh1 cells. The expansion of Tbet+ atypical B cells mediated by IFN-γ impairs BCR signaling and reduces the effector function. The high IL-10 production during malaria infection also inhibits macrophage responsiveness to IFN-γ and suppresses the microbicidal activity of macrophages to control bacterial growth. Malaria infection causes dysbiosis in the gut to increase the susceptibility to secondary infection. Sequestration of iRBC causes capillary breakage in the villi that drives the infiltration and activation of lymphocytes, neutrophils and mast cells to induce inflammation and disrupt the epithelial tight junctions. The epithelial damage increases the intestinal permeability that allows the invasion of bacteria from the gut. Consistent with the findings in malaria, recently a study on Mycobacterium tuberculosis showed similar activation of a subset of T cells that co-express IFN-γ and IL-10 during the chronic phase after day 21 post-infection, but not during the acute phase, and it was also partially dependent on both IFN-1 and IL-27 (67–69). Additionally, Plasmodium infection in mice suffering from chronic tuberculosis was shown to further dampen the immune responses against mycobacteria by enhancing IL-10 production in macrophages and T cells and inhibiting IFN-γ-mediated macrophage activation and nitric oxide production (69). Besides its effects on macrophages, chronic malaria may also affect neutrophil function as reduced neutrophil oxidative burst was observed among Gambian children with uncomplicated malaria (70). Mature neutrophils are an important anti-Plasmodium component of the host (71), but the induction of heme oxygenase-1 during malarial hemolysis increases the mobilization of immature neutrophils from the bone marrow that lack oxidative burst to kill the phagocytosed bacteria (72). However, the role of malaria is not solely on hemolytic anemia, as a mouse malaria model showed that hemolytic anemia only partially contributes to this susceptibility by suppressing macrophage microbicidal activity, while Plasmodium-specific factors play a more significant role by inducing IL-10 and down-regulating IL-12p70, which cause the impaired control of bacterial infection in gut mucosa (73–75). The gut serves as a vulnerable site for bacteria invasion during malaria. Malaria patients were commonly found to have mucosal edema and congestion accompanied by superficial bleeding, microthrombosis and gastric atrophy, which cause them to suffer from gastric symptoms including epigastralgia, nausea and vomiting (76). Plasmodium parasites were found to sequester in the small capillaries in the intestinal villi in autopsies of children who died of CM (77). Intestinal malabsorption and increased gastrointestinal permeability were prevalent in severe malaria cases (78, 79). The enhanced intestinal permeability was demonstrated, in a mouse model of malaria, to be associated with increased recruitment and activation of mast cells in the ileal villi and crypts, with elevated histamine and hypoargininemia (80). This study further showed that the disruption of the intestinal barrier increased the translocation of bacteria. The pathological damage caused by malaria in the gut has recently been shown to cause dysbiosis that alters the proportions of microbiota in the intestine (81). Malaria infection can breach mucosal immunity and affect the population of microbiota and vice versa (82, 83), thereby increasing the severity of pathology and risk of other infections (Fig. 2). Malaria as a cause of growth retardation and bone problems Most of the malaria-endemic areas are in lower socio-economy conditions, in which there is a lack of adequate healthcare, proper hygiene and nutritional practice that increases the morbidity of infections. The nutritional status could play a role in controlling the disease severity and overall outcome. For instance, a very recent study showed that a high-fat diet can exert a protective effect on liver-stage malaria infection (84). The disease severity and growth retardation in malaria-endemic regions have often been associated with malnutrition, but recent observations have brought to light the direct contribution of the malaria burden on physical growth in these regions (85). Although delayed skeletal maturation and prominent bone porosity were prevalent in these regions, it has been very difficult to determine whether malaria is the main cause of these bone defects (86, 87). A convincing study with proper control groups clearly showed that stunting and wasting were higher in children exposed to malaria compared with those protected from infection in the same community (88). Although these studies in human populations have suggested the potential suppressive effect of malaria on bone and growth development, recent mouse malaria models have confirmed the direct acute and the chronic effects of malaria infection on bone remodeling (89). This recent study showed that a single malaria infection can cause chronic bone loss long after recovery from infection (89). Accordingly, the acute and chronic phases of malaria infection have distinct mechanisms that eventually lead to the severe outcome—loss of bone. Initially, during acute malaria infection, the hemolysis and cytokine storm halted bone remodeling with inhibition of both osteoclast and osteoblast formation and activity, causing the initiation of bone loss. It is known that the absence of continuous bone replacement by bone remodeling may lead to an increase in microdamage and cracks due to mechanical stress on the bone (90). However, the chronic bone loss after recovery from malaria was found to be attributable to the continuous accumulation of Plasmodium products that elicit chronic inflammation through the activation of bone cell precursors via MyD88 signaling (89). The chronic inflammation mediates the up-regulation of the osteoclast differentiation factor, RANKL, on osteoblasts to promote osteoclast formation and hyper-activation (Fig. 3). Fig. 3. View largeDownload slide Hidden pathology of malaria within the bone. The long-term retention of Plasmodium products in the bone marrow changes the environment there. These Plasmodium products may interact directly with other bone marrow cells such as mesenchymal stromal cells and HSCs, or indirectly through cytokines to cause the alteration of bone marrow cellular composition and function. The accumulation of Plasmodium products in the bone marrow induces inflammation in osteoclast precursors, osteoblast precursors and mature osteoblasts. The inflammatory cytokines induce RANKL expression on mature osteoblasts to trigger activation of osteoclast formation which leads to an increased resorption activity and bone loss. Fig. 3. View largeDownload slide Hidden pathology of malaria within the bone. The long-term retention of Plasmodium products in the bone marrow changes the environment there. These Plasmodium products may interact directly with other bone marrow cells such as mesenchymal stromal cells and HSCs, or indirectly through cytokines to cause the alteration of bone marrow cellular composition and function. The accumulation of Plasmodium products in the bone marrow induces inflammation in osteoclast precursors, osteoblast precursors and mature osteoblasts. The inflammatory cytokines induce RANKL expression on mature osteoblasts to trigger activation of osteoclast formation which leads to an increased resorption activity and bone loss. These novel findings unveil one of the hidden pathologies within the bone tissue caused by malaria infection that raise our awareness of an unforeseen risk of bone pathology in malaria patients, especially those with chronic asymptomatic infections, repeated infections and relapses. How long the Plasmodium products remain in the bone marrow to cause tissue insult is, however, unknown as is whether their presence would affect bone marrow hematopoiesis. The underlying mechanisms of bone destruction during malaria infection could be multifactorial. Inflammation is known to contribute to hematopoietic stem cell (HSC) regulation and alter the bone marrow cellular composition (91); however, there is a lack of clear understanding of how the stress is sensed to bring about the changes in the bone marrow during malaria infection. Signals such as PAMPs or DAMPs (pathogen- or damage-associated molecular patterns) or cytokines might (1) be directly sensed by the HSC and cause a change in the transcriptome and differentiation, (2) induce apoptosis and expansion of certain progenitors or (3) change the bone marrow niche microenvironment through stromal cell alterations that indirectly influence HSC and osteogenic cells (92). Mesenchymal stromal cells constitute a large proportion in the bone marrow and play multiple roles in the regulation of bone remodeling, providing a conducive microenvironment in specific niches for blood cell production and development, and regulating the retention and mobilization of bone marrow cells. Malaria infection may affect stromal cell regulation either directly via recognition of the parasite antigen or its products, or indirectly by cytokine dysregulation that affects the osteogenic differentiation and expansion of myeloid progenitors in the bone marrow. Unlike other infectious diseases, malaria leaves its signature Plasmodium products in the bone marrow long term, even after recovery from infection, introducing foreign material into the bone marrow environment. It has been shown that osteoclasts, osteoblasts and their precursors directly respond to these Plasmodium products in the absence of on-going active infection (89). However, it remains to be explored how the other bone marrow cells interact and respond to these persistent parasite products and whether they have a role in modulating the bone marrow composition that affects hematopoiesis. Conclusions The pathology of malaria is more complex than we thought. Recent studies have revealed that there are still risks of unknown, unforeseen consequences of malaria that could link to various complications and diseases. The chronic, hidden complications might be among the obstacles for socio-economic development while hindering the malaria patients from living a normal, healthy life and to unleash their full potential for the development of their country (93). An overall health improvement may also decrease overall morbidity and mortality caused by other opportunistic diseases. Although treatments mainly focus on major complications, the possibility of chronic complications should be taken into consideration with follow-up examinations and adjunct therapies. Understanding the hidden cost of malaria can help to identify the early symptoms before the development of later complications and to determine the most suitable treatment for the disease. Conflicts of interests statement: The authors declare no competing interests. Acknowledgements These studies are supported by Grants-in-Aid for Scientific Research (KAKENHI KIBAN B grant no. 16H05181) and the Japan Agency for Medical Research and Development (AMED J-PRIDE 17fm0208021h0001). References 1 World Health Organization. 2016. World Malaria Report 2016 . World Health Organization, Geneva, Switzerland. 2 Rénia, L. and Goh, Y. S. 2016. Malaria parasites: the great escape. Front. Immunol . 7: 463. Google Scholar CrossRef Search ADS PubMed  3 Amino, R., Giovannini, D., Thiberge, S.et al.   2008. 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International ImmunologyOxford University Press

Published: Mar 1, 2018

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