key: cord-324953-3sacf4wu
authors: Childs, James E.; Richt, Jürgen A.; Mackenzie, John S.
title: Introduction: Conceptualizing and Partitioning the Emergence Process of Zoonotic Viruses from Wildlife to Humans
date: 2007
journal: Wildlife and Emerging Zoonotic Diseases: The Biology, Circumstances and Consequences of Cross-Species Transmission
DOI: 10.1007/978-3-540-70962-6_1
sha: 
doc_id: 324953
cord_uid: 3sacf4wu

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 unavailable to many zoonotic pathogens, (3) sustained human-to-human transmission and (4) genetic adaptation to the human host. The latter two transitions are presumably prerequisites for the pandemic emergence of a pathogen. The themes introduced herein are amplified 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 emergence the details and circumstances are never repetitive.

The process of zoonotic disease emergence can be understood by coupling knowledge of how zoonotic viruses have evolved and are maintained among their wildlife 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 underscores how disciplinary boundaries are blurred; advances require approaches spanning the spectrum of biological inquiry, and solutions to imminent threats require approaches unbounded by the notion of specific scientific discipline.

The emergence process involves ecological interactions at the individual, species, community, and global scale. The dynamic circumstances and relative importance of the participants reflect the evolutionary context in which zoonotic agents have become accommodated to, and been accommodated by, their reservoir hosts (H R 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 species distribution, abundance, and diversity, and are continually transforming the landscape of opportunity on which zoonotic viruses with their H R s mingle with novel, potentially susceptible secondary host species (H S )s (see the chapters 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 R s or H S s have heralded a sea change in how we view the public health threat posed by zoonotic viruses (Childs 2004) , as testified by the emergence of SARs coronavirus (SARS CoV) ; 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 ; see the chapter by Regnery, this volume).

Inherent in the term "cross-species transmission" (or spillover) is the ability for a foreign virus, once introduced into an individual of a H S population, to complete the virus infectious cycle: (1) adsorption, penetration, and uncoating, or separation 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 S cells is mediated by common or related cellular receptors. Additional bouts of infection following virus release from infected cells lead to the dissemination of virus throughout the host's tissue(s), precipitating, as a byproduct, pathologic alterations in the individual H S identifiable as symptomatic disease.

The pathogenic course of infection and disease within the secondary host (H S ) may bear little correspondence to the infectious process and outcome within the reservoir host (H R ). Oral lesions caused by herpesvirus B (CeHV-1) infection among individual macaques of the H R are transmogrified into an often fatal (~70%) meningoencephalitis in the human H S (Huff and Barry 2003) . Hantaviruses cause subclinical infections or subtle behavioral changes with limited pathology in individual rodents of species constituting the virus-specific H R s (Hinson 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 syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), developing in the human H S after virus spillover (Zaki et al. 1995; Tsai 1987) .

No matter how different the disease course among the human H S , the pathologic component of intra-H R transmission is highly relevant when considering 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 R s guarantees 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 ecologic 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 R with individuals of a susceptible H S and (2) cross-species transmission, a transition subsuming the complex interactions of the virus infectious cycle within the H S (Nayak 2000; Childs 2004 ). These first two transitions may require a mediating host such as an arthropod vector (H V ) or an intermediary vertebrate host (H I ); these additional host populations are readily accommodated by the modular emergence schema (Fig. 1 ).

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 virus between members of the new H S , subsequent to, and independent of, new spillover events, and (4) genetic adaptation and phenotypic changes accompanying sustained intra-H S transmission. Once sustained transmission 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 R . 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 .

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-tohuman transmission cycle mediated by anthropophilic H V s after introduction by bridging H V s feeding on infected primate H R s (de Silva et al. 1999; Wolfe 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 R appears in most cases to be critical to developing a virus with pandemic potential (Mims 1991 (Mims , 1995 . The introduction 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 accompanied 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 R s, or intermediate hosts (H I s) for SARS CoV (Lau et al. 2005; Song et al. 2005 ; see the chapter by Wang and Eaton, this volume).

To capture the rate at which outbreaks spread among hosts, epidemiologists have relied upon the reproduction potential, R 0 , as a measure of the expected number 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 0 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 taking alternative paths to emergence, with highly variable R 0 s are discussed below.

The underlying 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 Disease emergence can occur at the local and regional level or as a pandemic depending 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 R ) population, the schema is modular and readily accommodates inclusion of vector (H V ) populations and intermediate vertebrate host (H I or H 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 R population, in which a zoonotic virus or some other zoonotic pathogen circulates, and the bottom shaded box indicating the secondary host population (H S ) affected by pathogen spillover (assumed in most instances to be humans). The graded shaded pyramid within the H S population indicates that emergence often proceeds through a gradient of human population sizes and social connectivity. Spillover and human transmission 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 S population demarcated by the H S box. To the left of the population boxes are 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 R then directly through the H S 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 S transmission of the zoonotic pathogen (Transition 3) and, potentially, adaptation to the human host (e.g., SARs coronavirus). Sequential human-to-human transmission of a zoonotic pathogen at the local and regional scales is indicated by the series of broken white lines in the H S pyramid. Evolutionary forces can transform a zoonotic agent into a genetically distinct agent adapted to a new reservoir host, establishing the former H S as a new H R (e.g., SIV to HIV; avian influenza to pandemic human influenza). This transition and the modifying factors associated with the geographical location and context of the initial disease outbreak (white arrows in shaded H S 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 S population box to the right. Zoonotic pathogens may fail to initiate cross-species infection following exposures (top dashed line), fail to generate any additional infections within the H S (second dashed line), or experience epidemic fadeout when sustained human-to-human transmission fails and R 0 decreases below unity (third dashed line). The initial transition to sustained intra-H S transmission is prone to failure when populations are sparse or social connectivity is limited. (Modified from Childs 2004) 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.

Abiotic factors alter the potential for contact between H R and H S populations, 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 triggers 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 R or H V populations 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 leishmaniasis 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 vector-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 populations of H V s, driving enzootic transmission levels of western equine encephalomyelitis 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 ).

Intrinsic biotic and evolutionary factors enhance the ability of certain zoonotic viruses, notably those with RNA genomes (Cleaveland et al. 2001; Dobson and Foufopoulos 2001 ; see the chapters by Cleaveland et al. and by Holmes and Drummond, this volume) , to cross species barriers. Viruses with high replication 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 S (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 zoonotically acquired viruses are intermittently maintained among small and sparsely distributed human populations where R 0 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 limited 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 0 , and hence emergence (Antia et al. 2003) .

Additionally, 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 increasingly virulent viruses. When viruses of relatively low virulence are transmitted 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 alternative, evolutionarily stable situation (White et al. 2002; Boots et al. 2004 ).

Extrinsic biotic interactions, such as natural or human-assisted translocations of infected or latently infected individuals of H R or H V species have played an exaggerated role in the rapid emergence of zoonotic diseases within the last few years. Monkeypox transported with African rodents destined for the US pet trade (Centers for Disease Control and Prevention 2003; see the chapter by Regnery, this volume), globe-trotting humans infected with SARS-CoV ; see the chapter by Wang and Eaton, this volume), domestic dogs incubating rabies accompanying 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 R s and mosquito H V s. Certain bird species sustained WNV viremias of sufficient titer and duration to infect blood-feeding "bridge vectors" (Turell et al. 2001; Komar et al. 2003) , maintaining 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 V s and H R s in conjunction with the biogeography of avian migration aided the introduction and spread of WNV in Europe and the Middle East (Malkinson and Banet 2002) . By an alternate route of introduction, wind-blown infected mosquitoes may have introduced Japanese encephalitis virus (JEV) into northern mainland Australia in 1998 (Ritchie and Rochester 2001) .

As indicated above, many of the most important and widely cited factors modifying 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.

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) . Commercial farming operations inserted into clearings in forest habitats juxtapose 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 volume) , 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 vectorborne diseases such as JEV as mosquitoes and water bird H R 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) .

Species now linked by domestication to Homo sapiens provide rich fodder for evolutionary forays by zoonotic viruses into potential new hosts. The emergence 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 infection, 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 I s to humans (Barclay and Paton 2000; Chua et al. 1999 ). However, these two viruses also demonstrate the importance of transmissibility in the H I 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) .

Rabies virus associated with domestic dogs incubating infection and transported 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 Ethiopian wolves ( Canis simensis ) to 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 domesticated species have become efficiently enlisted as H I s or H R s, 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 I 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 opportunity for avian viruses to obtain the complement of genes required for their sustained transmission within mammalian hosts, such as humans (Suarez et al. 2002; Gibbs et al. 2001 ; see the chapter by Webby et al., this volume).

Significant 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 environments 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 availability have in instances increased the potential for human-animal-vector interactions. Later chapters illustrate how ecological changes have influenced 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).

Perhaps the most influential and certainly the most infamous anthropogenic modifiers driving the emergence process have been those enhancing social connectivity 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 presumed focus of human infection in the wet markets of Guangzhou, Guangdong 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 I or H R , on a journey destined 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.

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 humanto-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 

The schema 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 S. . .n ). The process outlined is similar to 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 nonindigenous species surviving transport and being introduced into a foreign environment;

(3) sustained intra-H S transmission of a zoonotic virus aligns with the establishment (self-perpetuation) of the invasive species within the new environment; and (4) sustained intra-H S transmission accompanied by evolutionary adaptation of the once zoonotic virus to a new H R , prior to emergence, aligns with adaptive radiation and spread of the invasive species beyond the local site of introduction (Grant et al. 2001 ).

The potential terminating points in the process of virus emergence or biological invasion (broken arrows leading outside of the H S 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 0 <1, aligns with "fails to establish"; and interruption of sustained intra-H S transmission, an average R 0 <1, aligns with "noninvasion" by the nonindigenous species. Differences between disease emergence and biological invasion exist, as transitions leading to disease emergence are not strictly hierarchical. Reiteration of contact and spillover (Fig. 1, transitions 1 and 2) at 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 repeatedly introduced to the site, further establishment and spread, prerequisites of invasion, is precluded. In addition to biological factors which establish the setting in which zoonotic 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 R s or H I 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.

Altering the environmental unit being invaded produces a radically different schema. The invasion process in Fig. 1 has an organismal or medical orientation, which can be transformed to a population or community orientation by regarding humans, rather than a zoonotic pathogen, as the invasive species. Human invasion of new habitats and new environments is a frequently cited factor in the emergence process of viral zoonoses (Morse 1995; Institute of Medicine 2003) . Where native H R s and H V s and their co-evolved viral 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 hantaviruses maintained by sigmodontine rodent H R s in North America (Monroe et al. 1999) , HIV resulting from transmission of SIVs circulating among nonhuman primate H R s in West Africa (Apetrei et al. 2004) , and NiV and HeV viruses from pteropid bat H R 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 spillover 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.

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). Predisposing biological characteristics include evidence of multiple H R 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 mutation 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) .

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 R s or infected H V s (WNV) for their transmission to the human H S . 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 positive selection , even where established within novel H R s or H V s . The term "evolutionary generalists" has been 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, mammalian, and insect H R s, H V s, and H S s. The rare instances of human-to-human transmission of these viruses are epidemiologically insignificant (Dietzschold and Koprowski 2004; Iwamoto et al. 2003) .

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 H V 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 R s and H V s, and dengue serotypes have become endemic among some suitably large human populations in Asia (Gubler 2002) .

Rabies virus crosses mammalian orders and species and can establish sustained transmission within new H R 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 striped 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 R s, rather than a homogeneous virus infecting multiple H R s; control or elimination of rabies in a specific H R 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 R (s) to sustain intra-H R transmission, with coincidental spillover to H S 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 R generally coincide with declines in incidental rabies epizootics among H S s (Gordon et al. 2004; Wandeler et al. 1974) . Epizootics can reemerge at periodic intervals as H R populations recover above the critical threshold density ( K T ) required to sustain virus transmission at R 0 >1 (Anderson et al. 1981; Childs et al. 2000; Coyne et al. 1989) .

In an analogous manner, epidemics caused by WNV involve reiterative introductions of infectious virus by any of a number of competent mosquito H V (s). WNV readily infects at least three classes of vertebrates (Avia, Mammalia, Reptilia) 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 certain epizootiologically dominant genetic clades have emerged, some with shorter extrinsic incubation periods within North American vectors 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 V s compared to tick H V s (Twiddy and Holmes 2003) .

The temperature and humidity requirements for survival and breeding of mosquito vectors, and the demand for temperature-sensitive extrinsic viral incubation within H V s, drive the strong seasonal transmission dynamics of 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) .

That SARS-CoV is new to science is not in question. However, the origin of SARS-CoV as a human pathogen arising from direct cross-species transmission 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 existing 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 ) that a long history of preexistence with its natural H R 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 Rhinolophidae. Genome sequence analysis indicated that SARS-like coronaviruses among these bats have an almost identical genome organization to those of SARS-CoVs isolated from humans or civets ; see the chapter by Wang and Eaton, this volume). These data suggest that bats serve as the H R of SARS-CoV and that palm civets served as a H S1 in a chain of events leading to infection of humans as secondarily infected H S2 . SARS-CoV's global emergence may be an extraordinary example of a relatively unmodified zoonotic virus, successfully sustained by intrahuman transmission. However, increasing data suggest SARS-CoV was a virus rapidly 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 indicate the degree of viral variation available for selection within the individual human. These findings are compelling evidence of evolutionary events underway, presaging the emergence 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 viral preadaptation permitting infection to occur among a broad range of H R s and H S 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 .

The biological 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 evolutionary path toward a R 0 sufficiently high to bypass these methods (Song et al. 2005; Antia et al. 2003; Fraser et al. 2004) .

The zoonotic viruses leading to potentially uncontrolled, pandemic health problems have adopted unique qualities associated with their sustained transmission within the human host. Adaptation to the human host may be mediated by viral preadaptation to a genetically similar intermediate host, as is hypothesized to occur among swine for avian-adapted influenza A subtypes (see the chapter by Webby et al., this volume). Permissive cells for subtype A influenza virus replication in the pig's respiratory track have cell-surface glycoprotein 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 R 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 R for HIV-2 was a sooty mangabey ( Cerocebus atys ) (Hirsch 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 "quasispecies" of viruses present in the infected H R at spillover. Sustained intrahuman transmission was accompanied by viral adaptations to the human host, readily detectable and quantifiable by sequence changes in the RNA genome and marked by qualitative phenotypic changes identifiable by host species preference and pathogenic interactions (Hirsch et al. 1989; Gao et al. 1999 ).

Evaluations of the genetic relatedness of HIV-1 and HIV-2 to SIVs circulating among nonhuman primates has led to wide acceptance that these distinctive 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 responsible 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 population size were insufficient to support a R 0 > 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 nonsterile needles (Gisselquist 2003) were presumably key anthropogenic factors increasing the level of social connectivity by providing HIV-infected individuals access to larger aggregates of susceptible hosts in cities (Apetrei et al. 2004 ).

The number of SIVs described among nonhuman primates in Africa as of 2004 was approximately 40 (Zhuang et al. 2002) . The biological capacity of lentiviruses includes rapid replication, high mutability, and the highest recorded rates of recombination known in virology. Knowledge of the frequency of potential opportunities for SIV spillover, based on transmission of a zoo of diverse simian foamy viruses during encounters between monkeys, apes, and human hunters in West Africa ) indicate transmission of blood-borne retroviruses is not rare. These facts highlight two important features of emergence; first, emergence is a process, not an event; second, the probability of new genetic lineages of human HIVs arising approximates unity. The same lessons apply to numerous other conditions which make up the body of this volume.

Environmentally driven epizootics

A case of severe monkeypox virus disease in an American child: emerging infections and changing professional values

Population dynamics of fox rabies in Europe

The role of evolution in the emergence of infectious diseases

Climate-disease connections: Rift Valley Fever in Kenya

The history of SIVS, AIDS: epidemiology, phylogeny and biology of isolates from naturally SIV infected non-human primates (NHP) in Africa

Molecular intermediates of fitness gain of an RNA virus: characterization of a mutant spectrum by biological and molecular cloning

Host switching in Lyssavirus history from the Chiroptera to the Carnivora orders

Hendra (equine morbillivirus)

Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes

Animal origins of SARS coronavirus: possible links with the international trade in small carnivoRes

El Nino and incidence of hemorrhagic fever with renal syndrome in China

Epidemiological evidence of higher susceptibility to vCJD in the young

Large shifts in pathogen virulence relate to host population structure

Comparative phylogenies of yellow fever isolates from Peru and Brazil

Evolvability of emerging viruses

Multistate outbreak of monkeypox-Illinois

Investigation of rabies infections in organ donor and transplant recipients

Rabies: decimation of a wolf pack in artic Alaska

Zoonotic viruses of wildlife: hither from yon

Effects of hantaviral infection on survival, growth and fertility in wild rat ( Rattus norvegicus ) populations of Baltimore Maryland

Predicting the local dynamics of epizootic rabies among raccoons in the United States

Public health surveillance and the molecular epidemiology of rabies

The influence of climate on the epidemiology of bartonellosis in Ancash Peru

Fatal encephalitis due to Nipah virus among pig-farmers in Malaysia

Pandemic influenza is a zoonosis, as it requires introduction of avianlike gene segments in the human population

Diseases of humans and their domestic mammals: pathogen characteristics, host range and the risk of emergence

Mathematic model for the population biology of rabies in raccoons in the mid-Atlantic states

Japanese encephalitis virus

Cluster of rabies cases of probable bat origin among red foxes in Prince Edward Island Canada

Anthropogenic environmental change and the emergence of infectious diseases in wildlife

Genetic variation among temporally and geographically distinct West Nile virus isolates United States

Serologic evidence for an epizootic dengue virus infecting toque macaques ( Macaca sinica ) at Polonnaruwa Sri Lanka

Rabies transmission from organ transplants in the USA

Emerging infectious pathogens of wildlife

History of epidemiological aspects of yellow fever

Identification of a novel coronavirus in patients with severe acute respiratory syndrome

Genetic and phenotypic variation of West Nile virus

Population monitoring in support of a rabies vaccination program for skunks in Arizona

The natural history of Hendra and Nipah viruses

Impact of the El Nino/Southern Oscillation on visceral leishmaniasis Brazil

Factors that make an infectious disease outbreak controllable

Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes

Rabies in African wild dogs ( Lycaon pictus ) in the Serengeti region Tanzania

The phylogeny of SARS coronavirus

The haemagglutinin gene, but not the neuraminidase gene, of 'Spanish flu' was a recombinant

Natural selection for resistance to epidemics

Emergence of the HIV type 1 epidemic in the twentieth century: comparing hypotheses to evidence

Satellite imagery characterizes local animal reservoir populations of Sin Nombre virus in the southwestern United States

Two rabies deaths after corneal grafts from one donor

West Nile virus update: a new route of transmission is found

Temporal dynamics of rabies in a wildlife host and the risk of cross-species transmission

Origins, evolution, and vector/host coadaptations within the genus Flavivirus

A population founded by a single pair of individuals: establishment, expansion, and evolution

Emerging and resurging vector-borne diseases

The global emergence/resurgence of arboviral diseases as public health problems

AIDS as a zoonosis: scientific and public health implications

Concepts of infectious disease epidemiology

Japanese encephalitis in North Queensland

The international response to the outbreak of SARS in

Wounding: the primary mode of Seoul virus transmission among male Norway rats

An African primate lentivirus (SIVsm) closely related to HIV-2

Rapid evolution of RNA genomes

Viral evolution and the emergence of SARS coronavirus

Genetic constraints and the adaptive evolution of rabies virus in nature

B-virus ( Cercopithecine herpesvirus 1) infection in humans and macaques: potential for zoonotic disease

Microbial threats to health; emergence, detection, and response

Transmission of West Nile virus from an organ donor to four transplant recipients

Effect of irrigated rice agriculture on Japanese encephalitis, including challenges and opportunities for integrated vector management

El Nino Southern Oscillation and Ross River virus outbreaks in Australia

Wildlife and pastoral society--shifting paradigms in disease control

Progress in invasion biology: predicting invaders

Experimental infection of North American birds with the New York 1999 strain of West Nile virus

A novel coronavirus associated with severe acute respiratory syndrome

Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome

Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States

Complete genome sequences and phylogenetic analysis of West Nile virus strains isolated from the United States

Hunting and logging linked to emerging infectious diseases

Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats

Climate and satellite indicators to forecast Rift Valley fever epidemics in Kenya

Bats are natural reservoirs of SARS-like coronaviruses

Vector-borne viral diseases and climate change in the Australian region: major concerns and the public health response

Ross River virus isolations from mosquitoes in arid regions of Western Australia: implication of vertical transmission as a means of persistence of the virus

Historical intensity of natural selection for resistance to tuberculosis

SARS transmission pattern in Singapore reassessed by viral sequence variation analysis

Histopathology of Peromyscus leucopus naturally infected with pathogenic NY-1 hantaviruses: pathologic markers of HPS infection in mice

The ecology of infectious disease: effects of host diversity and community composition on Lyme disease risk

Invasions by insect vectors of human disease

West Nile virus and other zoonotic viruses in Russia: examples of ermerging-reemerging situations

Japanese encephalitis as an emerging virus: the emergence and spread of Japanese encephalitis virus in Australasia

Emerging flaviviruses: the spread and resurgence of dengue Japanese encephalitis and West Nile viruses

The role of birds in the ecology of West Nile virus in Europe and Africa

Infectious disease dynamics: What characterizes a successful invader

The origin of major human infections and the crucial role of personto-person spread

Virology research and virulent human pandemics

Nipah virus infection of pigs in peninsular Malaysia

Yellow fever

Genetic diversity and distribution of Peromyscus -borne hantaviruses in North America

Factors in the emergence of infectious diseases

Virus morphology, replication, and assembly

Possible role of an animal vector in the SARS outbreak at Amoy Gardens

Emerging viral diseases

A method for predicting Murray Valley encephalitis in southeast Australia using the southern oscillation

Transmission of the severe acute respiratory syndrome on aircraft

Severe acute respiratory syndrome: review and lessons of the 2003 outbreak

Incidence of plague associated with increased winter-spring precipitation in New Mexico

The emergence of bovine spongiform encephalopathy and related diseases

Unhealthy landscapes: Policy recommendations on land use change and infectious disease emergence

Human Diseases with Natural Foci (Translated from Russian by D Rottenberg)

Migratory birds modeled as critical transport agents for West Nile virus in North America

Trigger events: enviroclimatic coupling of Ebola hemorrhagic fever outbreaks

When is a trophic cascade a trophic cascade

SARS associated coronavirus has a recombinant polymerase and coronaviruses have a history of host-shifting

Transmission dynamics of the etiological agent of SARS in Hong Kong: impact of public health interventions

Wind-blown mosquitoes and introduction of Japanese encephalitis into Australia

A canine distemper virus epidemic in Serengeti lions ( Panthera leo )

Characterization of a novel coronavirus associated with severe acute respiratory syndrome

Vector competence of three North American strains of Aedes albopictus for West Nile virus

Genetic susceptibility to infectious disease

Drought-induced amplification of Saint Louis encephalitis virus Florida

Rabies and mortality in Ethiopian wolves ( Canis simensis )

Nipah virus infection in swine

Epidemiologic and historical relationships among 87 rabies virus isolates as determined by limited sequence analysis

Cross-host evolution of severe acute respiratory syndrome coronavirus in palm civet and human

Isolation from turkey breeder hens of a reassortant H1N2 influenza virus with swine, human, and avian lineage genes

Hemorrhagic fever with renal syndrome: clinical aspects

Vector competence of North American mosquitoes (Diptera: Culicidae) for West Nile virus

The extent of homologous recombination in members of the genus Flavivirus

Rabies in wild carnivores in central Europe. I. Epidemiological studies

El Nino and the related phenomenon Southern Oscillation (ENSO): The largest signal in interannual climate variation

Relationships among weather, mosquito abundance, and encephalitis virus activity in California: Kern County 1990-1998

Epidemiological consequences of a pathogen having both virulent and avirulent modes of transmission: the case of rabbit haemorrhagic disease virus

Reduced positive selection in vector-borne RNA viruses

Sylvatic transmission of arboviruses among Bornean orangutans

Naturally acquired simian retrovirus infections in central African hunters

Natural cycles of vector-borne pathogens

Evidence of airborne transmission of the severe acute respiratory syndrome virus

Hantavirus pulmonary syndrome. Pathogenesis of an emerging infectious disease

Testing the hypothesis of a recombinant origin of the SARS-associated coronavirus

Human immunodeficiency virus type 1 recombination: rate, fidelity, and putative hot spots