Introduction: Conceptualizing and Partitioning the Emergence Process of Zoonotic Viruses from Wildlife to Humans

James E. Childs; Jürgen A. Richt; John S. Mackenzie

doi:10.1007/978-3-540-70962-6_1

Childs, James E.; Richt, Jürgen A.; Mackenzie, John S.

0168-03-01 00:00:00

CTMI (2007) 315:1–31 © Springer-Verlag Berlin Heidelberg 2007 Introduction: Conceptualizing and Partitioning the Emergence Process of Zoonotic Viruses from Wildlife to Humans 1 2 3 J. E. Childs · J. A. Richt · J. S. Mackenzie (* ü ) Department of Epidemiology and Public Health , Yale School of Medicine , 60 College St. , P.O. Box 208034 New Haven , CT 06520-8034 , USA Veterinary Medical Officer, National Animal Disease Center , 2300 Dayton Ave , Ames , IA 50010 , USA Premier’s Research Fellow, Australian Biosecurity CRC , Curtin University of Technology , GPO Box U1987 Perth , WA , Australia 6845 [email protected] 1 Introduction ....................................................................................................... 2 1.1 Cross-Species Transmission (Spillover) ............................................................. 3 1.2 Pathogenesis in the Reservoir Host and Secondary Host ................................. 3 2 The Comparative Ecology of Zoonosis Emergence and Species Invasion .......................................................................................... 4 2.1 Four Transition Stages to Emergence: The First Two Are Prerequisite ............ 4 2.2 Two Transition Stages Are Required for Pandemic Emergence ........................ 4 2.3 The Basic Reproductive Potential R as a Measure of Viral Relative Fitness ...................................................................................... 6 3 Modifying Factors in the Emergence Process ................................................. 6 3.1 Abiotic Factors in Emergence ............................................................................. 8 3.2 Evolutionary and Intrinsic Biotic Factors in Emergence .................................. 8 3.3 Extrinsic Biotic Interactions in Emergence ....................................................... 10 3.4 Anthropogenic Influences as a Special Class of Extrinsic Factors in Emergence .......................................................................................... 10 3.4.1 Habitat Modification, Human Encroachment, and Modern Agricultural Practices .......................................................................................... 11 3.4.2 Domestic Animals Provide a Bounty of Novel Niches ...................................... 11 3.4.3 Human Population Demographics and Urbanization ...................................... 12 3.4.4 The Miracle of Modern Transport ..................................................................... 13 3.4.5 The Miracle of Modern Medicine ...................................................................... 13 4 Invasion Biology as a Paradigm for Disease Emergence ................................ 16 4.1 Termination Points and Pitfalls on the Route to Emergence or Invasion ........ 16 4.2 Human Invaded or Human Invader? ................................................................. 17 2 J. E. Childs et al. 5 Qualities of Zoonotic Viruses Emerging by Different Transition Routes ............................................................................................... 18 5.1 Emergence Via Reiterative Processes of Contact and Spillover ........................ 18 5.2 Spillover Subsequently Sustained by Human-to-Human Transmission.......... 18 5.3 The Road to Human Adaptation: A Still-Life with SARS CoV? ....................... 20 5.4 Adaptation of Zoonotic Viruses to the Human H and Pandemic Emergence ........................................................................................................... 21 References ....................................................................................................................... 22 Abstract This introduction provides a telegraphic overview of the processes of zoonotic viral emergence, the intricacies of host–virus interactions, and the distinct role of biological transitions and modifying factors. The process of emergence is conceptualized as two transition stages which are common and required for all disease emergence, (1) human contact with the infectious agent and (2) cross-species transmission of the agent, and two transition stages which are not required for emergence and appear unavail- able to many zoonotic pathogens, (3) sustained human-to-human transmission and (4) genetic adaptation to the human host. The latter two transitions are presumably prerequi- sites for the pandemic emergence of a pathogen. The themes introduced herein are ampli- fied and explored in detail by the contributors to this volume. Each author explores the mechanisms and unique circumstances by which evolution, biology, history, and current context have contrived to drive the emergence of different zoonotic agents by a series of related events; although recognizable similarities exist among the events leading to emer- gence the details and circumstances are never repetitive. Introduction The pr ocess of zoonotic disease emergence can be understood by coupling knowl- edge of how zoonotic viruses have evolved and are maintained among their wild- life hosts, transmitted across a species barrier to cause productive infection in a taxonomically distinct secondary host, initiate a pathologic process causing disease, and, by repetitive infection within the secondary host species, result in incident morbidity or mortality of sufficient magnitude to be detected and characterized as a novel health concern of local, regional, or global significance (see the chapter by Childs, this volume). Obviously, we possess no such knowledge for any zoonotic virus or zoonotic disease, but casting the emergence process in this context under- scores how disciplinary boundaries are blurred; advances require approaches span- ning the spectrum of biological inquiry, and solutions to imminent threats require approaches unbounded by the notion of specific scientific discipline. The emergenc e process involves ecological interactions at the individual, species, community, and global scale. The dynamic circumstances and relative Introduction 3 importance of the participants reflect the evolutionary context in which z oonotic agents have become accommodated to, and been accommodated by, their reservoir hosts (H s) (see the chapters by Cleaveland et al. and by Holmes and Drummond, this volume), the diversity of reservoir species involved, their geographic ranges and the local dispersion of host and pathogen populations. In turn, historical factors have modified and blurred traditional patterns of spe- cies distribution, abundance, and diversity, and are continually transforming the landscape of opportunity on which zoonotic viruses with their H s mingle with novel, potentially susceptible secondary host species (H )s (see the c hap- ters by Daszak et al., Field et al., Regnery, and Wang and Eaton, this volume). The current historical circumstances are unprecedented in their efficiency for continually shuffling an expanding repertoire of zoonotic viruses and hosts, introducing them in novel ecologic circumstances to a wealth of previously unavailable and unexplored niches. Within the last decade, the accelerated pace of rapid translocations of infected H s or H s have heralded a sea change in R S how we view the public health threat posed by zoonotic viruses (Childs 2004), as testified by the emergence of SARs coronavirus (SARS CoV) (Drosten et al. 2003; see the chapter by Wang and Eaton, this volume), influenza A subtype H5N1 (Peiris et al. 2004; see chapter by Webby et al., this volume), West Nile virus (WNV) (Lanciotti et al. 1999), Nipah virus (NiV) (Chua et al. 1999; see the chapter by Field et al., this volume), and Monkeypox virus (Anderson et al. 2003; see the chapter by Regnery, this volume). 1.1 Cross-Species Transmission (Spillover) Inherent in the term “cross-species transmission” (or spillover) is the ability for a foreign virus, once introduced into an individual of a H population, to complete the virus infectious cycle: (1) adsorption, penetration, and uncoating, or separa- tion of the viral nucleic acid from the capsid; (2) transcription, translation, and replication, and; (3) assembly and release (Nayak 2000). Binding and entry into permissive H cells is mediated by common or related cellular receptors. Addi- tional bouts of infection following virus release from infected cells lead to the dis- semination of virus throughout the host’s tissue(s), precipitating, as a byproduct, pathologic alterations in the individual H identifiable as symptomatic disease. 1.2 Pathogenesis in the Reservoir Host and Secondary Host The pathogenic course of infection and disease within the secondary host (H ) may bear little correspondence to the infectious process and outcome within the 4 J. E. Childs et al. reservoir host (H ). Oral lesions caused by herpesvirus B (CeHV-1) infection among individual macaques of the H are transmogrified into an often fatal (~70%) meningoencephalitis in the human H (H uff and Barry 2003). Hantaviruses cause subclinical infections or subtle behavioral changes with limited pathology in individual rodents of species constituting the virus-specific H s (H inson et al. 2004; Llyubsky et al. 1996; see the chapter by Klein and Calisher, this volume), accompanied by no notable loss of fitness (Childs et al. 1989). However, these subtleties are lost in the severe and often fatal hemorrhagic fever with renal syn- drome (HFRS) and hantavirus pulmonary syndrome (HPS), developing in the human H after virus spillover (Zaki et al. 1995; Tsai 1987). No matter how different the disease course among the human H , the patho- logic component of intra- H t ransmission is highly relevant when consider- ing strategies to prevent human infection rather than treating post-spillover disease (see the chapter by Daniels et al., this volume). Ignoring the intricacies of zoonotic virus transmission among wildlife H s guar antees that solutions springing from a traditional anthropocentric disease-treatment/vaccine-preventative approach will consider a limited universe of defensive prevention targets and generate a restricted arsenal of intervention tools . The Comparative Ecology of Zoonosis Emergence and Species Invasion 2.1 Four Transition Stages to Emergence: The First Two Are Prerequisite The ec ologic process of zoonotic disease emergence can be schematized by four transition stages (Fig. 1 ), of which only the first two are prerequisites for emergence: (1) contact between infectious propagules originating from the wildlife H w ith individuals of a susceptible H and (2) cr oss-species transmis- R S sion, a transition subsuming the complex interactions of the virus infectious cycle within the H (N ayak 2000; Childs 2004). These first two transitions may require a mediating host such as an arthropod vector (H ) or an intermediary vertebrate host (H ); these additional host populations are readily accommo- dated by the modular emergence schema (Fig. 1). 2.2 Two Transition Stages Are Required for Pandemic Emergence The latter two transition stages demarcate a change in the interrelationship of host and virus (Fig. 1): (3) sustained transmission of the once zoonotic Introduction 5 virus between members of the new H , subsequent to, and independent of, new spillover events, and (4) genetic adaptation and phenotypic changes accompanying sustained intra-H t ransmission. Once sustained trans- mission occurs within the human host, evolutionary adaptation between virus and host can transform the once zoonotic virus into a distinctive new virus with a new human H . The new virus associated with humans must be quantitatively and qualitatively different from ancestral strains in genetic and phenotypic characters, in order to designate the emergence of a new biological entity. With HIV and pandemic influenza subtypes, the qualities of the newly adapted viruses to humans are readily apparent in terms of host preference and host pathogenicity (Hahn et al. 2000; Claas 2000). With SARS CoV infecting humans, the specific genetic changes are less clear-cut (Song et al. 2005), most probably because the transmission of SARS CoV was curtailed early its relationship to the new human host. Support for this conclusion is based on the genetic differences accrued by SARS CoVs sustained through multiple generations of human-to-human transmission as compared with those viruses with shorter interhuman passages (Liu et al. 2005). Some viruses are capable of sustained human-to-human transmission with minimal or no genetic change [i.e., SARS CoV; see the chapter by Wang and Eaton, this volume, although limits to genetic adaptation within humans may be imposed by the requirement for an intermediate vector or extensive prior adaptation to a specific reservoir host (Gould et al. 2003)]. The arboviruses, yellow fever virus, and the four dengue serotypes circulate in a human-to- human transmission cycle mediated by anthropophilic H s aft er introduction by bridging H s feeding on infected primate H s (de Silva et al. 1999; Wolfe V R et al. 2001; Monath 1989; Downs 1982); these viruses appear closely related to the wild type viruses circulating in sylvatic cycles, although regional variation is apparent (Bryant and Barrett 2003). Viral adaptation to the human H appears in most cases to be critical to developing a virus with pandemic potential (Mims 1991, 1995). The intro- duction of avian-like gene segments into preexisting, aerosol-transmitted, human influenza A viruses, or alternatively, the introduction of key genetic components into preexisting avian viruses (see the chapter by Webby et al., this volume) may be prerequisite to pandemic influenza A emergence (Claas 2000). The emergence of SARS into the human population was accompa- nied by strong and rapid positive selection of different subtypes of virus as indicated by comparisons of sequence data from humans and from palm civets and rhinolophid bats, putative H s, or intermediate hosts (H s) for SARS R I CoV (Lau et al. 2005; Song et al. 2005; see the chapter by Wang and Eaton, this volume). 6 J. E. Childs et al. 2.3 The Basic Reproductive Potential R as a Measure of Viral Relative Fitness T o capture the rate at which outbreaks spread among hosts, epidemiologists have relied upon the reproduction potential, R , as a measure of the expected num- ber of secondarily infected and infectious hosts produced during the infectious period of a single infected host when introduced into a freely mixing population of susceptible individuals (Halloran 1998). The relative fitness defined by R is a composite of three terms c, the contact rate or number of contacts per unit time, p , the transmission probability per contact, and d, the duration of infectiousness (see the chapter by Real and Biek, this volume). Examples of zoonotic viruses tak- ing alternative paths to emergence, with highly variable R s are discussed below. Modifying Factors in the Emergence Process The underly ing feature distinguishing modifying factors (Fig. 1, right panel) from transition stages in zoonotic virus emergence (Fig. 1, left panel) is that the former requires the substrate provided by the latter on which to act. Modifying Fig. 1 A schema for partitioning the process of zoonotic disease emergence into four transitions and modifying factors which alter the likelihood of transitions occurring. Disease emergence can occur at the local and regional level or as a pandemic depend- ing on the nature of the pathogen and the influence of modifying factors. Modifying factors are largely responsible for driving the magnitude and geographic scope of an emergent event, but by themselves are insufficient to lead to disease emergence. Although only a single population source for a zoonotic pathogen is indicated, the reservoir host (H ) population, the schema is modular and readily accommodates inclusion of vector (H ) populations and intermediate vertebrate host (H or H ) V I S 1 populations antecedent to spillover to humans (see Fig. 1 in the chapter by Childs, this volume). Transition stages, with the exception of contact (Transition 1) and cross-species transmission (spillover; Transition 2), are not strictly hierarchical in the emergence process. Transition stages are shown to the left of the population boxes and the two transitions required for emergence (contact and spillover) are shaded gray. In the center are two population boxes, the top shaded box indicating a H popula- tion, in which a zoonotic virus or some other zoonotic pathogen circulates, and the bottom shaded box indicating the secondary host population (H ) affected by patho- gen spillover (assumed in most instances to be humans). The graded shaded pyramid within the H population indicates that emergence often proceeds through a gradient of human population sizes and social connectivity. Spillover and human transmis- sion chains in remote villages (apex of pyramid) can lead to spread to urban centers (base of pyramid), at which point a pathogen is assumed to have access to the entire H population demarcated by the H box. To the left of the population boxes are S S Introduction 7 EXAMPLES OF MODIFYING FACTORS CONTACT Reservoir Species invasion/human introduction Host (H ) H , H pop. density/H species diversity R S R Population Type of utilization of H or H by the other R S Multi-host arthropod vectors Zoonotic Agent No cross-spp. CROSS-SPECIES TRANSMISSION transmission Quasi-species diversity/RNA genome Conserved viral receptors among H , H R S No secondary Disease pathogenesis/altered behavior Secondary transmission Health (nutritional, immune) of individual H Host (H ) S within H Pop. SUSTAINED INTRA-H TRANSMISSION Pathogenesis/mode of virus excretion Superspreaders Aggregation of H , H , & vectors Local extinction R S Population Anthropogenic influences Density & R <1 - urbanization Social -social interconnectivity, rapid transport Distance Gradient H ADAPTATION LOCAL OR Pathogen mutation & replication rate REGIONAL Frequency/type of recombination EMERGENCE Number of intra-H generations increases R S O GLOBAL EMERGENCE Repeated H H introductions R S Sustained Intra H transmission Fig. 1 Continued examples of modifying factors. Contact and spillover are sufficient to result in disease emergence at the local, regional, or even continental scale through reiterative introductions, as exemplified by zoonotic diseases such as rabies or West Nile fever. The two solid black lines with arrowheads leading from the H then directly through the H to local or regional emergence (the first emergence box) represent reiterative events as a pathway to emergence. Two other transitions not essential for emergence, but critical to pandemic disease emergence, require sustained intra-H transmission of the zoonotic pathogen (Transition 3) and, potentially, adaptation to the human host (e.g., SARs coronavirus). Sequential human-to-human transmis- sion of a zoonotic pathogen at the local and regional scales is indicated by the series of broken white lines in the H pyramid. Evolutionary forces can transform a zoonotic agent into a genetically distinct agent adapted to a new reservoir host, establishing the former H as a new H (e.g., SIV to HIV; avian influenza to pandemic human influ- S R enza). This transition and the modifying factors associated with the geographical loca- tion and context of the initial disease outbreak (white arrows in shaded H cone) can ultimately precipitate a pandemic emergence (e.g., HIV and pandemic influenza). The process of emergence for any zoonotic pathogen can fail at a minimum of three points, indicated by the labeled dashed lines with arrowheads leading out of the H population box to the right. Zoonotic pathogens may fail to initiate cross-species infection following exposures (top dashed line), fail to generate any additional infec- tions within the H (second dashed line), or experience epidemic fadeout when sus- tained human-to-human transmission fails and R decreases below unity (third dashed line). The initial transition to sustained intra-H transmission is prone to failure when populations are sparse or social connectivity is limited. (Modified from Childs 2004) FOUR TRANSITIONS TWO NON-ESSENTIAL TWO ESSENTIAL but required for pandemic emergence for any emergence 3. SUSTAINED INTRA H TRANSMISSION 4. No. 3 & H ADAPTATION 2. SPILLOVER 1. CONTACT 8 J. E. Childs et al. factors alter the likelihood of a transition occurring and drive the geographic spread and determine the magnitude of morbidity and mortality resulting from a particular instance of emergence. 3.1 Abiotic Factors in Emergence A biotic factors alter the potential for contact between H and H populations, R S or infectious intermediaries, and modulate the potential for spillover; zoonotic diseases highly dependent on abiotic factors are often labeled environmentally driven epizootics (Allen and Cormier 1996). On a global scale, climate change has been increasingly linked to instances of zoonotic disease emergence, with El Nino Southern Oscillation (ENSO) providing the largest interannual signal of climate variation (Wang et al. 1999). One hypothesized mechanism by which ENSO trig- gers increased incidence of zoonotic disease among humans, is through a chain of sequentially induced events referred to as a trophic cascade (Polis et al. 2000), ultimately leading to increased numbers of individuals among H or H popula- R V tions and increasing the risk of human exposure to a zoonotic pathogen (Nicholls 1986; Kelly-Hope et al. 2004; Bi and Parton 2003; Glass et al. 2002; Anyamba et al. 2001). ENSO events have been correlated with increased risk of HPS and plague in the southeastern United States (Glass et al. 2002; Parmenter et al. 1999), increased infection by Ross River virus in Australia (Lindsay and Mackenzie 1997; Kelly-Hope et al. 2004), and arthropod-vectored Bartonella bacilliformis and visceral leishmani- asis in South America (Chinga-Alayo et al. 2004; Franke et al. 2002). Local weather conditions, potentially driven by global climate variation, have been repeatedly shown to influence the emergence of zoonotic and vec- tor-borne viruses. Drought can serve to amplify enzootic transmission of St. Louis virus (Shaman et al. 2002) and possibly Japanese encephalitis (Hanna et al. 1999; Mackenzie et al. 2002) and Ebola viruses (Pinzon et al. 2004; see the chapter by Gonzalez et al., this volume), ultimately placing humans at higher risk for spillover. The converse, excessive rainfall, can increase breeding popula- tions of H s, driving enzootic transmission levels of western equine encephalo- myelitis virus, Ross River virus, and Rift Valley fever virus to heightened levels, and ultimately increasing zoonotic virus spillover to humans (Lindsay et al. 1993; Wegbreit and Reisen 2000; Linthicum et al. 1999). 3.2 Evolutionary and Intrinsic Biotic Factors in Emergence Intrinsic biotic and evolutionary factors enhance the ability of certain zoonotic viruses, notably those with RNA genomes (Cleaveland et al. 2001; Dobson and Introduction 9 Foufopoulos 2001; see the chapters by Cleaveland et al. and by Holmes and Drummond, this volume), to cross species barriers. Viruses with high replica- tion rates, high mutation rates, and increased potential for recombination or reassortment may more readily adapt to new fitness landscapes and become transmitted among humans to emerge as pandemic threats (Burke 1998; Nichol et al. 2000); examples include HIV and subtypes of Influenza A (Hahn et al. 2000; Claas, 2000; see the chapter by Webby et al., this volume). The intrinsic genetic variability in susceptibility to infectious diseases within the human H (Segal and Hill 2003) is further modulated by an individual’s cumulative life experience and history of infection by various pathogens, reflected by acquired immunological memory or, possibly, an individual’s ancestry and evolutionary imprint of prior exposure to pathogens (Gillespie 1975; Lipsitch and Sousa 2002). Furthermore, immunologic function and the susceptibility of individual humans to infection and disease are dynamic and vary with factors such as nutritional status and age (Boelle et al. 2004). Strong evolutionary forces may be in play in circumstances where zoonoti- cally acquired viruses are intermittently maintained among small and sparsely distributed human populations where R may hover close to unity. In theory, virus evolution is affected by socially structured host populations, such as where some human populations are aggregated in remote villages, with lim- ited opportunity for social interchange. Models of virus transmission which assume homogeneous or freely mixing populations are of limited use in such circumstances. In such settings, modest increases in the number of generations of human-to-human transmission sustained by a new virus prior to fadeout (Fig. 1, second terminal dotted line) improves the likelihood of virus evolution to a higher average R , and hence emergence (Antia et al. 2003). A dditionally, sparsely distributed populations where contact rates, c , between infectious and susceptible individuals are low can support bistable evolutionary dynamics. One trend leads to the rapid evolution of increas- ingly virulent viruses. When viruses of relatively low virulence are transmit- ted among dispersed metapopulations of hosts, the result can be a cluster of infected individuals surrounding an index case, which is rapidly transformed into a semi-impermeable barrier of immune individuals (Boots et al. 2004), effectively terminating additional transmission. Virulent viruses causing lethal infections leave no immune survivors to block transmission and, in the course of removing infected individuals, further enhance the sparseness of the existing social structure. In situations where viruses of relatively low virulence circulate, the introduction of a highly virulent virus strain, either through an infected immigrant or from viral recombination, can alter the evolutionary trajectory of virus–host adaptation favoring selection for increasing virulence and an alter- native, evolutionarily stable situation (White et al. 2002; Boots et al. 2004). 10 J. E. Childs et al. 3.3 Extrinsic Biotic Interactions in Emergence Extrinsic biotic interactions, such as natural or human-assisted translocations of infected or latently infected individuals of H or H species ha ve played an exag- R V gerated role in the rapid emergence of zoonotic diseases within the last few years. Monkeypox transported with African rodents destined for the US pet trade (Cen- ters for Disease Control and Prevention 2003; see the chapter by Regnery, this vol- ume), globe-trotting humans infected with SARS-CoV (Olsen et al. 2003; see the chapter by Wang and Eaton, this volume), domestic dogs incubating rabies accom- panying human colonialists (see the chapter by Nel and Rupprecht, this volume), and the stowaway mosquito, bird, or human infected with WNV (Lanciotti et al. 2002) bear witness to the growing problems of a shrinking interconnected world (see the chapter by Daszak et al., this volume). Mosquito-borne viral diseases have resulted from the introduction of exotic viruses into indigenous local populations of mosquitoes previously not involved as vectors (Lanciotti et al. 2002), in addition to the establishment and spread of exotic mosquito species harboring viruses into new geographic locations (Lounibos 2002; Mackenzie et al. 2004). However, not all biological invasions or disease introductions survive to cause epidemics, as was the case with SARS and monkeypox in North America. In contrast, WNV was an entirely different matter. The rapid establishment and spread of WNV in North America was nearly assured by the presences of indigenous species of competent wild bird H s and mosquito H s. Certain R V bird species sustained WNV viremias of sufficient titer and duration to infect blood-feeding “bridge vectors” (Turell et al. 2001; Komar et al. 2003), maintain- ing transmission to humans and spreading WNV as migrating birds followed traditional flyways (Peterson et al. 2003). The same extrinsic phenomena of a community of seemingly preadapted and widely available potential H s and H s in conjunction with the biogeography of avian migration aided the intro- duction and spread of WNV in Europe and the Middle East (Malkinson and Banet 2002). By an alternate route of introduction, wind-blown infected mos- quitoes may have introduced Japanese encephalitis virus (JEV) into northern mainland Australia in 1998 (Ritchie and Rochester 2001). 3.4 Anthropogenic Influences as a Special Class of Extrinsic Factors in Emergence A s indicated above, many of the most important and widely cited factors modi- fying the scope and scale of zoonotic disease emergence are anthropogenic in origin; a few examples are described to highlight their importance and their distinctiveness from required transition stages. Introduction 11 3.4.1 Habitat Modification, Human Encroachment, and Modern Agricultural Practices Human population growth and modern agricultural practices have enticed human settlers into clearing patches within ecosystems of maximally high biodiversity, such as tropical rain forests, converting substantial areas into cultivated fields and pastures (Patz et al. 2004; LoGiudice et al. 2003). Com- mercial farming operations inserted into clearings in forest habitats juxta- pose and intermingle humans and livestock with native animal populations (Kock et al. 2002; Daszak et al. 2001; see the chapter by Field et al., this vol- ume), and, coincidentally, with whatever zoonotic pathogens exist within these natural nidi (Pavlovsky1957). In many instances, the cleared land has been used for irrigated agriculture, resulting in an increase in vector- borne diseases such as JEV as mosquitoes and water bird H s are brought in close proximity to domestic pigs in nearby villages (Morse 1995; Keiser et al. 2005). Dams are built to maintain water for human consumption and for use in irrigated agriculture, but they too may lead to increased zoonotic disease emergence as they provide the milieu for intermingling mosquito vectors and reservoir hosts of arboviruses as well as the spread of other diseases such as schistosomiasis. Modern agricultural practices have also provided the mechanism by which bovine spongiform encephalopathy emerged in the United Kingdom in the early 1980s (Pattison 1998). 3.4.2 Domestic Animals Provide a Bounty of Novel Niches Species no w linked by domestication to Homo sapiens pr ovide rich fodder for evolutionary forays by zoonotic viruses into potential new hosts. The emer- gence of zoonotic viruses among humans or domestic livestock where our species has drifted into preexisting sylvatic foci of zoonotic viruses is driven by local circumstance, history, and serendipity. The role of livestock, such as horses and pigs, can be pivotal in a transmission chain leading to human infec- tion, as illustrated by the henipaviruses (see the chapters by Daniels et al. and Field et al., this volume). NiV and HeV first jumped the species barrier to infect pigs and horses, respectively, and only then were transmitted by these H s to humans (Barclay and Paton 2000; Chua et al. 1999). However, these two viruses also demonstrate the importance of transmissibility in the H s influencing the ultimate emergence of human disease; NiV was readily transmitted among pigs while HeV was rarely transmitted among horses or from horse to human (see the chapter by Daniels et al., this volume). 12 J. E. Childs et al. Rabies virus associated with domestic dogs incubating infection and t ransported with humans was the likely source of endemic cycles of rabies involving most terrestrial mammals in North and South America and in many areas of Africa (Childs et al. 2002; Smith et al. 1992; see the chapter by Nel and Rupprecht, this volume). In addition to causing an estimated 50,000 human deaths annually, rabies virus associated with domestic dogs have driven naïve indigenous populations of African wild dogs ( Lycaon pictus) and E thiopian wolves ( Canis simensis) t o the threshold of extinction and caused declines among other large carnivore populations (Roelke-Parker et al. 1996; Sillero- Zubiri et al. 1996; Gascoyne et al. 1993; Chapman 1978; see the chapter by Nel and Rupprecht, this volume). Other domesticat ed species have become efficiently enlisted as H s or H s, I R in a bridging process leading to human disease. Swine production management practices have improved the efficacy of this economically important livestock species as an amplifying H for JEV and NiV transmission to humans (Daniels et al. 2002; Singh and Jamaluddin 2002; Mohd Nor et al. 2000; see the chapter by Field et al., this volume). Swine may also serve as the mammalian mixing vessel for influenza A viruses of domestic and wild birds, offering the oppor- tunity for avian viruses to obtain the complement of genes required for their sustained transmission within mammalian hosts, such as humans (S uarez et al. 2002; Gibbs et al. 2001; see the chapter by Webby et al., this volume). 3.4.3 Human Population Demographics and Urbanization S ignificant changes in the demography of global human populations during the past five decades have been driven not only by population growth, but by changes in population distribution and social structuring brought about by migration, the ongoing movement of persons from rural to urban environ- ments and the resettlement of refugees. The concentration of humans in the urban environment has given rise to mega-cities where a large proportion of persons may live in substandard conditions in marginal areas, sometimes referred to as shanty towns, surrounding the urban core. The crowded living conditions within shanty towns are further degraded by poor sanitation and lack of water; these conditions have been associated with the emergence of diseases, notably those involving vector-transmitted pathogens (Gratz 1999; Gubler 2002; Mackenzie et al. 2004). Urban and periurban changes in land use have altered the availability and quality of habitat available to wildlife, and ecological changes in resource avail- ability have in instances increased the potential for human–animal–vector interactions. Later chapters illustrate how ecological changes have influenced Introduction 13 the abundance and accessibility of wildlife species serving as reservoir hosts for different pathogens, leading to the emergence of zoonotic pathogens associated with pteropid bats (see the chapter by Field et al., this volume) and white-tailed deer (see the chapter by Paddock and Yabsley, this volume). 3.4.4 The Miracle of Modern Transport P erhaps the most influential and certainly the most infamous anthropogenic modifiers driving the emergence process have been those enhancing social con- nectivity through road construction (Larkin 2000), railroads, and, the crown jewel of rapid modern transport, jet plane-assisted travel (Fig. 1; Childs 2004; see the chapter by Daszak et al., this volume). Nowhere has the role of rapid transportation been more evident than with SARS CoV (Table 1 ), where a pre- sumed focus of human infection in the wet markets of Guangzhou, Guang- dong Province, China, where live animals or their products are available for purchase, was transformed into a global health problem affecting 27 nations on every populated continent (Heymann 2004; see the chapter by Wang and Eaton, this volume). The human SARS CoV appears to have been inadvertently transported to a wet-market, along with an infected H or H , on a journey des- I R tined to end with human consumption (Bell et al. 2004). Wildlife farming and an immense network of illegal national and international trade in wildlife has been fueled by human demands for wildlife products of unusual culinary or putative medicinal properties (Bell et al. 2004). These cultural propensities enriched the range of opportunities for novel host/zoonotic virus interchange, but alone, as with rapid transport of persons, would not have resulted in a case of SARS without the biological capabilities of the virus to readily establish spillover. 3.4.5 The Miracle of Modern Medicine Modern medical practices requiring the widespread use of needles, increased application of immunosuppressive therapies, organ transplant, and blood transfusions have contributed substantially to the spread and emergence of zoonotic pathogens (Institute of Medicine 2003; see the chapter by Paddock and Yabsley, this volume). In certain exceptional instances, medical technology has permitted zoonotic viruses, generally limited in their capacity for human- to-human transmission, to flirt briefly with the transmission route prerequisite to pandemic emergence (Fig. 1). Illustrative of this phenomena were instances of WNV and rabies virus transmission from infected donors to susceptible recipients receiving blood transfusion (WNV) and organ and tissue transplants 14 J. E. Childs et al. Table 1 Examples of transitions and modifying factors in zoonotic disease emergence; SARS CoV and HIVs Transition Initial context and circumstances Examples of modifying factors Contact between H Coronaviruses extant among sylvatic species ● Wildlife consumed as culinary delicacies or medicinal or infectious propagules of mammals and birds purposes; national and international trade in wildlife from H and H ● Increased connectivity between humans in remote sites R S to cities via public and commercial roads (logging, min- Coronaviruses extant among commensal and ing, etc.); increased availability of ground domestic animals, and humans raising poten- transportation tial for coinfection or superinfection ● Rapid transportation of game animals to national and international markets SIVs circulate in at least 40 species of nonhu- ● Concentration of diverse wildlife species, domestic man primates in West Africa, most of which animals and humans in wet markets are used for human consumption. High poten- ● Exposure to animal blood and tissues during butchering tial for retrovirus transmission through contact by humans and during predation by animals with primate blood as indicated by infection of humans with primate foamy viruses Cross-species SARS CoV infected several orders ● RNA genomes, most notably retroviruses, capable of transmission of mammals in wet markets of China high-frequency mutation and recombination. High intrahost genetic diversity provides wide range of genotypic/phenotypic viral variants for selection by SIVs circulating in nonhuman primates H during spillover are often mosaics of several SIV subtypes, ● SARS CoV ability to infect multiple orders of mammals indicating contact and recombination suggests evolution has of a viral “generalist” preadapted among nonhuman primate H s for species invasion ● Close taxonomic relationship between H and H may R S facilitate viral adaptation once SIV has been introduced into individuals of H ● Contact with blood and other tissues containing high titers of virus ensured by use of H s as food by human H R S Introduction 15 Sustained intra-H Once SARS CoV or HIV established within a ● SARS CoV pathology in H results in respiratory S S transmission human H , access to urban setting with high transmission by droplet or possibly aerosols density of susceptibles increases potential for ● Superspreader phenomena average R > 1 ● Increased number of intrahuman passages may have increased R of SARS CoV Respiratory transmission of SAR CoV ● Medical technology (reused nonsterile needles, blood transfusion, etc.) provides new routes of transmission for HIV Long period of infectiousness without overt clinical disease contribute to high R with HIV High degree of within individual diversity Sustained intra-H ● Rapid international transport of infected persons of HIV viral subtypes driven by immune transmission and with SARS or HIV pressure adaptation to H and ● Recombination may have produced novel SARS CoV global emergence adapted to humans Long period of infectiousness prior to clinical ● Poor surveillance and reporting in China slowed disease increase number of intrahuman control measures passages of HIV ● SARS controlled by traditional public health measures (quarantine, isolation of exposed persons, etc.) because infectiousness and disease coincident (pandemic averted) Infectiousness of SARS CoV coincides with ● Reparatory transmission aided SARS CoV spread clinical disease and peaks several days after ● Sexual transmission and high R assured HIV global disease onset spread 16 J. E. Childs et al. (WNV and rabies virus) (Iwamoto et al. 2003; Goldrick 2003; Centers for Disease Control and Prevention 2004; Gode and Bhide 1988). These rare instances involved transient, human-to-human transmission of viruses normally requir- ing a mosquito vector (WNV) or direct contact (rabies virus) for their trans- mission. Medical interventions limited further transmission, although biologic constraints inherent to the virus and host would have self-limited any sustained human-to-human transmission. Invasion Biology as a Paradigm for Disease Emergence The sc hema for emerging diseases (Fig. 1) emphasizes viral interactions within the newly colonized secondary host, of which humans may be but one of several susceptible species (H ). The process outlined is similar to S. . .n the schema developed to characterize biological invasions by nonindigenous species (Kolar and Lodge 2001). The transition states proposed for emerging diseases and those for invasive species are largely parallel: (1) contact with infectious propagules aligns with the nonindigenous species in a transport pathway to a foreign shore; (2) cross-species transmission aligns with the non- indigenous species surviving transport and being introduced into a foreign environment; (3) sustained intra-H t ransmission of a zoonotic virus aligns with the establishment (self-perpetuation) of the invasive species within the new environment; and (4) sustained intra-H t ransmission accompanied by evolutionary adaptation of the once zoonotic virus to a new H , prior to emergence, aligns with adaptive radiation and spread of the invasive species beyond the local site of introduction (Grant et al. 2001). 4.1 Termination Points and Pitfalls on the Route to Emergence or Invasion The potential terminating points in the process of virus emergence or biological invasion (broken arrows leading outside of the H population block in Fig. 1) are consequences of similar circumstances. Failure to cross the species barrier (spillover) aligns with “fails in transport”; failure to sustain transmission, with a transmission potential, R <1, aligns with “fails to establish”; and interruption of sustained intra-H t ransmission, an average R <1, aligns with “noninvasion” S 0 by the nonindigenous species. Differences between disease emergence and bio- logical invasion exist, as transitions leading to disease emergence are not strictly hierarchical. Reiteration of contact and spillover (Fig. 1, transitions 1 and 2) at Introduction 17 sufficiently high levels can suffice for a disease to emerge, but if an invading species never moves and perishes at the site of its introduction, even if repeat- edly introduced to the site, further establishment and spread, prerequisites of invasion, is precluded. In addition to biological factors which establish the setting in which zoo- notic pathogens may emerge (see the chapters by Cleaveland et al. and Daszak et al., this volume), the emergence of a zoonotic agent within human or animal populations must be detected by humans. Too often the presence of a zoonotic agent is first identified by the presence of disease in humans, and surveillance for disease emergence is largely restricted to identifying incident cases of disease in humans rather than monitoring infection or disease among wildlife H s or H s (see the chapters by Childs, by Merianos, and by Stallknecht, this volume). The challenges present to designing programs aiming to disrupt transmission of a zoonotic pathogen within a wildlife reservoir host population prior to spillover and disease emergence are discussed in the chapters by Childs and by Stallknecht in this volume. 4.2 Human Invaded or Human Invader? Altering the environmental unit being invaded produces a radically different schema. The invasion process in Fig. 1 has an organismal or medical orienta- tion, which can be transformed to a population or community orientation by regarding humans, rather than a zoonotic pathogen, as the invasive spe- cies. Human invasion of new habitats and new environments is a frequently cited factor in the emergence process of viral zoonoses (Morse 1995; Insti- tute of Medicine 2003). Where native H s and H s and their c o-evolved viral R V pathogens exist in natural foci (Pavlovsky 1957), enhanced opportunities for novel ecologic interactions await. Initial instances of emergence have proven unpredictable as exemplified by HPS resulting from transmission of hantavi- ruses maintained by sigmodontine rodent H s in N orth America (Monroe et al. 1999), HIV resulting from transmission of SIVs circulating among non- human primate H s in West Africa (Apetrei et al. 2004), and NiV and HeV viruses from pteropid bat H s in Asia and Australia (Field et al. 2001). Herein, we stress the organismal– medical orientation, humans colonized or invaded by zoonotic viruses. Human intrusion into novel environments is regarded as an anthropogenic factor which modifies the likelihood of contact and spill- over transitions occurring. However, without the preexisting sylvatic zoonotic cycle, human invasion alone would not engender the first case of illness along the path to emergence. 18 J. E. Childs et al. Qualities of Zoonotic Viruses Emerging by Different Transition Routes Insights as to why and how certain zoonotic viruses appear predisposed to spillover and the various paths they take in the emergence process, are to be gleaned by examining the evolutionary history and current context of where and how zoonotic viruses exist and just how they become identified as etiologic agents of human disease (see the chapter by Childs, this volume). Predispos- ing biological characteristics include evidence of multiple H s (Dobson and Foufopoulos 2001; Cleaveland et al. 2001; see the chapters by Cleaveland and by Holmes and Drummond, this volume), high replication rates, high muta- tion rates, and the potential for homologous or heterologous recombination, which reach maxima in zoonotic viruses with RNA genomes (Holland et al. 1982; Arias et al. 2001). 5.1 Emergence Via Reiterative Processes of Contact and Spillover Two zoonotic viruses with histories of reemergence are rabies virus and WNV, both of which depend solely, with the exception of rare instances mentioned above, on repetitive contact and spillover between infected H s or infected H s R V (WNV) for their transmission to the human H . Although the RNA genomes of these two zoonotic viruses are markedly different in terms of organization, polarity, and replication strategy, both viruses show evidence of reduced posi- tive selection (Woelk and Holmes 2002), even where established within novel H s or H s (H olmes et al. 2002). The term “evolutionary generalists” has been R V applied to both viruses as they share, to some extent, the requirement of being able to infect and multiply within cells belonging to different species and, in the case of vector-borne WNV, the need to infect and multiply within avian, mam- malian, and insect H s, H s, and H s. The rare instances of human-to-human R V S transmission of these viruses are epidemiologically insignificant (Dietzschold and Koprowski 2004; Iwamoto et al. 2003). 5.2 Spillover Subsequently Sustained by Human-to-Human Transmission Although humans are, with few exceptions, incidental hosts for zoonotic viruses emerging from sylvatic transmission cycles, a few zoonotic arboviruses can be maintained by human-to-human transmission mediated by anthropophilic vectors in urban settings where large populations of humans and competent Introduction 19 H s coexist, particularly in environments with poor sanitation and overcrowding. Yellow fever virus (Wolfe et al. 2001; de Silva et al. 1999) and dengue virus serotypes (Kuiken et al. 2003; Ksiazek et al. 2003) are arboviruses where major epidemics are associated with urban transmission cycles rather than sporadic spillover from sylvatic H s and H s, and dengue serotypes have become endemic among R V some suitably large human populations in Asia (Gubler 2002). Rabies v irus crosses mammalian orders and species and can establish sus- tained transmission within new H s (Badrane and Tordo 2001), as has been observed on several occasions where bat-associated variants of rabies virus have achieved temporary sustained transmission among terrestrial carnivores, such as red foxes ( Vulpes vulpes) and st riped skunks ( Mephitis mephitis) (Daoust et al. 1996; Engeman et al. 2003). The maintenance of rabies virus, considered a single species of Lyssavirus, serotype 1/genotype 1, is achieved as a myriad of distinct viral variants maintained within different specific mammalian H s, rather than a homogeneous virus infecting multiple H s; control or elimina- tion of rabies in a specific H may be achieved but the diversity of host–virus dyads is a formidable buffer against any overall elimination scheme. Epidemics of rabies virus are sustained when there are sufficient individuals of the primary H (s) to sustain intra-H transmission, with coincidental spill- R R over to H s by reiterative introductions by inoculation of infectious virus in saliva. As rabies is fatal among most mammalian species, population declines among the principal H gener ally coincide with declines in incidental rabies epizootics among H s (Gordon et al. 2004; Wandeler et al. 1974). Epizootics can reemerge at periodic intervals as H populations r ecover above the criti- cal threshold density ( K ) required to sustain virus transmission at R >1 T 0 (Anderson et al. 1981; Childs et al. 2000; Coyne et al. 1989). I n an analogous manner, epidemics caused by WNV involve reiterative intro- ductions of infectious virus by any of a number of competent mosquito H (s). WNV readily infects at least three classes of vertebrates (Avia, Mammalia, Rep- tilia) and mosquito species, and some species of ticks (Gould et al. 2003; Komar et al. 2003; Lvov et al. 2004; Sardelis et al. 2002; Turell et al. 2001). Although WNV appears to be reasonably homogeneous in regions of North America over time, geographic clustering of genetically similar strains is detectable and cer- tain epizootiologically dominant genetic clades have emerged, some with shorter extrinsic incubation periods within North American vectors (Davis et al. 2003; Ebel et al. 2004). Subtleties associated with host–vector–virus relationships are being uncovered, such as the greater frequency of Flavivirus recombination among mosquito H s compared to tick H s (Twiddy and Holmes 2003). V V The t emperature and humidity requirements for survival and breeding of mosquito vectors, and the demand for temperature-sensitive extrinsic viral incubation within H s, drive the strong seasonal transmission dynamics of V 20 J. E. Childs et al. WNV and other arboviral diseases. With the onset of cold temperatures in temperate zones, WNV transmission ceases and epidemics of human disease desist (Woodring et al. 1996). 5.3 The Road to Human Adaptation: A Still-Life with SARS CoV? That SARS-C oV is new to science is not in question. However, the origin of SARS-CoV as a human pathogen arising from direct cross-species transmis- sion of a preexisting, but previously unknown virus (Gibbs et al. 2004; Holmes and Rambaut 2004; see the chapters by Holmes and Drummond and by Wang and Eaton, this volume) or as a virus formed from the recombination of exist- ing mammalian and avian coronaviruses (Rest and Mindell 2003; Zhang et al. 2004) has been the subject of debate. SARS- CoV is sufficiently distinct in genetic sequence from previously known coronaviruses (Rota et al. 2003) that a long history of preexistence with its natural H population is surmised (Parashar and Anderson 2004). Recently, coronaviruses related to SARS-Cov have been amplified by PCR from three communal cave-dwelling species of the genus Rhinolophus in the family Rhinolo phidae. Genome sequence analysis indicated that SARS-like coronaviruses among these bats have an almost iden- tical genome organization to those of SARS-CoVs isolated from humans or civets (Li et al. 2005; see the chapter by Wang and Eaton, this volume). These data suggest that bats serve as the H of SARS-CoV and that palm civets served as a H in a chain of events leading to infection of humans as secondarily S1 infected H . SARS-CoV’s global emergence may be an extraordinary example S2 of a relatively unmodified zoonotic virus, successfully sustained by intrahuman transmission. However, increasing data suggest SARS-CoV was a virus rap- idly adapting to its new human host and the rapid and effective public health response terminating its transmission halted an evolutionary dramas in the making (see the chapter by Wang and Eaton, this volume). Genetic sequence data indicate that strong positive selection accompanied SARS-CoV’s emergence and that distinctive human-associated changes in the genome distinguish virulent SARS-CoV from isolates of virus from palm civets (Song et al. 2005). Additional data indicate genetic changes were accompanying longer chains of human-to-human transmission. Heterogeneous viral sequences recovered from a single patient’s samples (Liu et al. 2005) indicate the degree of viral variation available for selection within the individual human. These findings are compelling evidence of evolutionary events underway, presaging the emer- gence of a virus with a unique genetic signature associated with its human host. Whatever the exact origin of SARS-CoV, the genetic endowments of this virus facilitated cross-species infection. An evolutionary history that includes Introduction 21 viral preadaptation permitting infection to occur among a broad range of H s and H s is suggested by SARS CoV’s ability to infect a range of mammalian orders (Ng 2003; Song et al. 2005; Bell et al. 2004). Such preadaptation can be assumed to have endowed SARS-CoV with a suite of traits readily adaptable for establishing sustained intrahuman transmission (Riley et al. 2003; Isakbaeva et al. 2004). Pathogenesis within the novel human host’s respiratory tissues offered an efficient means for sustained transmission by expressed droplets, or possibly aerosol (Yu et al. 2004). The biolog ical properties of SARS-CoV, the human behaviors and societal practices which increased the likelihood of contact and spillover and the rapid transport of already infected individuals drove the trajectory of the emergence of this global health problem. The distinctions and critical interactions between required biological transitions and modifying factors are clearly illuminated by this emergence process (Fig. 1, Table 1). Fortunately, SARS-CoV was effectively controlled by tried and true public health measures serving to increase social distance and diminish infectious contacts, c , perhaps curtailing a rapid evolu- tionary path toward a R sufficiently high to bypass these methods (Song et al. 2005; Antia et al. 2003; Fraser et al. 2004). 5.4 Adaptation of Zoonotic Viruses to the Human H and Pandemic Emergence The z oonotic viruses leading to potentially uncontrolled, pandemic health problems have adopted unique qualities associated with their sustained trans- mission within the human host. Adaptation to the human host may be mediated by viral preadaptation to a genetically similar intermediate host, as is hypoth- esized to occur among swine for avian-adapted influenza A subtypes (see the chapter by Webby et al., this volume). Permissive cells for subtype A influ- enza virus replication in the pig’s respiratory track have cell-surface gly- coprotein receptors recognized by some avian-adapted viruses, in addition to some human-adapted influenza viruses (Basler et al. 2001). In the case of HIV, the H for SIVs giving rise to HIV-1 was our closest living genetic relative, the chimpanzee ( Pan troglodytes troglodytes) (Gao et al. 1999), and the H for HIV - 2 was a sooty mangabey ( Cerocebus atys) (H irsch et al. 1989), a respectfully close relative of the order Primates. Spillover was enhanced by the enormous population of candidate viruses within the genetically heterogeneous “quasi- species” of viruses present in the infected H at spil lover. Sustained intrahuman transmission was accompanied by viral adaptations to the human host, read- ily detectable and quantifiable by sequence changes in the RNA genome and marked by qualitative phenotypic changes identifiable by host species prefer- ence and pathogenic interactions (Hirsch et al. 1989; Gao et al. 1999). 22 J. E. Childs et al. Evaluations of the genetic relatedness of HIV-1 and HIV-2 to SIVs circulating among nonhuman primates has led to wide acceptance that these distinc- tive human lentiviruses, now globally distributed in humans, originated from cross-species transmission in the not so distant past, perhaps within the first half of the twentieth century (May et al. 2001). The human lentiviruses, HIV-1 and HIV-2, have evolved and escaped from remote African settings on at least eight independent occasions to emerge as distinctive genetic subtypes respon- sible for regional or pandemic human disease (Apetrei et al. 2004; B. Hahn, personal communication). These recognized cases of emergence are certainly not the first instances where SIVs have successfully crossed species and evolved as distinctive HIVs of humans. Early emergences were likely restricted to local occurrences in remote locations where human contact rates, c , and popula- tion size were insufficient to support a R > 1, even if infections were of a long duration, d; such occurrences would be highly prone to transmission fadeout (Fig. 1). Road construction, automotive transport, and, perhaps, reuse of non- sterile needles (Gisselquist 2003) were presumably key anthropogenic factors increasing the level of social connectivity by providing HIV-infected individu- als access to larger aggregates of susceptible hosts in cities (Apetrei et al. 2004). The n umber of SIVs described among nonhuman primates in Africa as of 2004 was approximately 40 (Zhuang et al. 2002). 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Wildlife and Emerging Zoonotic Diseases: The Biology, Circumstances and Consequences of Cross-Species Transmission Pubmed Central

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Introduction: Conceptualizing and Partitioning the Emergence Process of Zoonotic Viruses from Wildlife to Humans

Childs, James E.; Richt, Jürgen A.; Mackenzie, John S.

Wildlife and Emerging Zoonotic Diseases: The Biology, Circumstances and Consequences of Cross-Species Transmission , Volume 315 – Mar 1, 168

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