Zoonotic viruses of wildlife: hither from yon

J. E. Childs*

Viral and Rickettsial Zoonoses Branch, National Center for Infectious Diseases, Centers for Disease Control and Prevention,

Atlanta, Georgia, U.S.A.

Summary. The emergence of zoonotic viruses maintained by wildlife reservoir hosts is poorly understood. Recent discoveries of Hendra (HENV) and Nipah (NIPV) viruses in Australasia and the emergence of epidemic West Nile virus (WNV) in the United States have added urgency to the study of cross-species transmission.

The processes by which zoonotic viruses are transmitted and infect other species are examined as four transitions. Two of these, inter-species contact and cross-species virus transmission (spillover), are essential and sufficient to cause epidemic emergence. Sustained transmission and virus adaptation within the spillover host are transitions not required for virus emergence, but determine the magnitude and scope of subsequent disease outbreaks. Ecologic, anthropogenic, and evolutionary factors modify the probability that viruses complete or move through transitions. As surveillance for wildlife diseases is rare and often outbreak­driven, targeted studies are required to elucidate the means by which important zoonotic viruses are maintained and spillover occurs.

Introduction

Human encephalitides caused by zoonotic viruses are unfortunate, but incidental occurrences. With rare exceptions, humans do not contribute to the maintenance of viruses circulating among wildlife populations; viruses may be repeatedly introduced, but most only briefly colonize the human host.

An appreciation that specific human-animal interactions - a bite received from a deranged dog - preceded the onset of certain diseases - a progressive delirium followed by death - was chronicled in ancient texts from Mesopotamia and China; these unmistakable descriptions of rabies encephalitis indicate some humans were quite familiar with zoonotic viruses by the second millennium B.C. [1]. A renewed

*Current address: Department of Biology and Program in Population Biology and Evolutionary Ecology, Emory University, 1510 Clifton Road, Atlanta, Georgia 30345, USA

C.H. Calisher et al. (eds.), Emergence and Control of Zoonotic Viral Encephalitides

© Springer-Verlag Wien 2004

2 J. E. Childs

interest in zoonotic viruses maintained by wildlife was kindled by near-coincident discoveries of novel viruses, HENV, NIPV, and a bat-associated lyssavirus [22], causing fatal human encephalitis in Australasia, and by the forceful reminder provided by WNV in the United States [20] of how rapidly exotic vector-borne viruses can spread when introduced into receptive new environments. Interest has led to assessment. What is our core understanding of how zoonotic viruses are maintained in wildlife? How and when do these viruses cross species barriers? Where and why do certain viruses emerge on a global scale? Assessment has led to new public health activities and research, but glaring deficiencies in our global capacity to detect outbreaks and to diagnose zoonotic diseases have been exposed. Efforts to improve detection and diagnosis of human and domestic animal diseases are important, but alone they will contribute little to the broader objectives to elucidate natural maintenance cycles and to limit future cross-species transmission of zoonotic viruses. Although there are effective vaccines that protect against zoonotic encephalitides (e.g. rabies and Japanese encephalitis [JED, developing additional new vaccines and identifying human populations to vaccinate remain daunting challenges. Ultimately, in the effort to reduce the risk of human exposure, most prevention and control programs for zoonotic diseases are predicated upon knowledge of wildlife reservoirs and arthropod vectors.

Transitions: wildlife infection to human zoonosis

Emergence of zoonotic viruses of wildlife is a complex and poorly understood process. Several loosely related phenomena are typically grouped under the rubric of "emerging disease": new diseases caused by new pathogens, increased disease incidence of pre-existing pathogens, or diagnosis of extant disease caused by a pre-existing but previously undetected pathogen [16]. Herein, the focus is on two transitions essential for successful cross-species introduction of a zoonotic virus and two other transitions influencing the magnitude and scope (e.g., sporadic, epidemic, or pandemic) of emergence. In an analogous manner, invasion biologists differentiate the transitions required of exotic species successfully overcoming dispersal barriers such as transport, introduction, establishment, and invasion

Fig. 1. The emergence of a zoonotic virus maintained by a reservoir host (HR; top gray box) requires transmission (solid black arrow) to a secondary host population (Hs; lower gray box), which may exist as local, partially isolated communities or demes (graded dark cone within the Hs population box). The process of emergence is partitioned into four transitions (left vertical scale); two, contact and spillover (cross-species transmission) are required for all emerging viruses, and reiterations of virus through these transitions (indicated and marked as the long solid arrow) is sufficient for emergence (e.g., WNV and rabies virus). Transitions to sustained intra- Hs transmission (broken solid line leading to emergence), and virus spread and possible adaptation to Hs, establish limits to the scope and magnitude of virus emergence (sporadic, epidemic, pandemic). Broken lines leading outside of population boxes indicate failure to complete the transition or local extinction. Examples of factors that modify the probability of a virus completing a transition are listed to the right

Wildlife and zoonotic viruses 3

[17]. An important conceptual distinction is that successive completion of each transition (i.e. a strict transition hierarchy) is not required for a zoonotic virus to emerge.

The two essential transitions for virus emergence are: 1) contact between infectious products (e.g., secretions, tissues, vectors, fomites, etc.) generated by a reservoir host (HR) and susceptible individuals of the secondary host (Hs) and 2) cross-species transmission of virus from HR to Hs, defined by introduc­tion, replication, and release of virus from the Hs (Fig. 1). Recurrence of these

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4 J. E. Childs

two transitions is sufficient to cause epidemic emergence (e.g. WNV and rabies virus).

The two transitions establishing the scope and magnitude of emergence are 3) sustained intra-Hs transmission of virus and: 4) subsequent spread of virus among the Hs with or without adaptations indicating Hs -specific evolution. These two transitions are the likely prerequisites of pandemic emergence [25], and the processes by which viruses are introduced and by which sustained intra-Hs transmission occur require differentiation [26).

Increasing the odds for emergence

Aspects of the virus, host, and environment modulate the level of opportunity afforded to hosts and pathogens to mix, produce cross-species infections, and generate disease (Fig. 1).

The profile of a virus successfully crossing the species barrier and establishing sustained intra-Hs transmission might include I) an RNA genome providing high mutability (N.B. the novel coronavirus associated with severe acute respiratory disease (SARS) provides a notable exception [19]), 2) a genome segmentation permissive to reassortment upon superinfection, 3) a genetic predisposition to recombine, 4) a high replication rate providing adaptive potential, 5) a high transmission rate achieved by direct or vector-borne spread, and 6) virus main­tenance among multiple-RHs (multiple reservoir hosts) indicative of high innate invasiveness [4, 6]. These characteristics reflect the evolutionary history of the RH and the virus. However, in the process of emergence, virus life-history traits derived in an evolutionary context now remote may predispose success in a Hs.

Characters modifying the susceptibility of a Hs to cross-infection at the in­dividual or population level include; taxonomic relatedness to the HR; genetic background (e.g. MHC) and constitutive factors permitting virus attachment, uptake, replication, and release from Hs cells, immune modifiers such as age, stress, and nutritional status, and previous or existing infection by antigenically­related viruses or by pathogens affecting immune functions.

Most zoonotic viruses crossing the species barrier cause sporadic disease or self-limited local outbreaks in a Hs. When secondary infections produced by spillover events fail to replace themselves by repeated reintroduction or sustained intra-Hs transmission (i.e., the reproduction rate of the pathogen, Ro, is less than 1), epidemics are self-limited. Each case of human or domestic animal rabies typically results from a new introduction of virus from an infected, terminally ill animal; as rabies removes individuals from the HR population, the corresponding risk of rabies spillover to Hs may decline [2, 34]. In temperate climes epidemics of West Nile fever decline with the onset of cold weather.

Once cross-species transmission has occurred, anthropogenic and ecological factors, such as rapid transport, agricultural-farming practices, medical technolo­gies, and habitat encroachment, modification and degradation become the classes of transition modifiers most frequently cited as leading to emergence [8, 26, 30). However, other factors also are crucial. The tissue tropism and pathogenesis

Wildlife and zoonotic viruses 5

of infections in the HR and Hs influences the likelihood of virus spillover and subsequent intra-Hs transmission. Differences in the pathology and pathogenesis of NIP V in pigs (HSl; first secondary host) and HENV in horses greatly influenced the transition to sustained intra-Hsl transmission of NIPV, as described below. When assessing the pandemic threat posed by an emerging virus, the potential to cause respiratory infection with airborne spread is uniquely important [25].

Ecological and environmental factors act at each transition, modifying the likelihood of species contact, influencing the potential for cross-species virus transmission, and enhancing or retarding disease spread. Seasonal migrations of birds introduce WNV [23] and alter the population densities ofHRs. Warmer tem­peratures may shorten the prerequisite extrinsic incubation period of arboviruses in vectors. Local rainfall or snowmelt influence vector breeding success and global climatic factors, such as the El Nino Southern Oscillation [21], affect regional weather patterns modifying species interactions at different trophic levels [10]. Droughts may force aggregation of wildlife reservoir hosts and vectors, enhancing opportunities for virus transmission [31].

The emergence of NIPV in Malaysia illustrates the interplay of essential transitions and modifying factors. Anthropogenic factors have been credited as the primary elements in NIPV emergence; deforestation and pig farming practices established high-density aggregates of pigs interspersed within habitat frequented by flying foxes (Pteropus spp.). Humans disseminated NIPV-infected pigs be­tween local communities and to international markets [8]. These factors greatly increased potential contact between bats (HR) and pigs (Hs), between infected and susceptible pigs, and between infected pigs (Hsd and humans (HS2; second secondary host). However, successful NIPV transitions to spillover and sustained intra-Hsi transmission were the antecedents magnified by subsequent human activities.

Although the molecular basis is yet to be established, the rapid transitions posted by NIPV presumably were mediated by genetic endowments enhancing virus capacity to cross species-barriers. A larger genome, dissimilar from other members of the virus family Paramyxoviridae, warranted placement of HEN V and NIPV within a new genus, Henipavirus. The ability of these viruses to colonize new hosts, as attested to by NIPV transmission to five mammalian Orders (Chiroptera, Carnivora, Perissodactyla, Artiodactyla, and Primata), also appears unique [33]. In pigs, NIPV infection can cause a severe, sometimes fatal, respiratory disease and also meningoencephalitis [14]. The initial tissue tropism of NIPV in pigs was probably endothelial tissue, with subsequent dis­semination or further adaptation of the virus to replicate in neurons and res­piratory epithelium [14]. Respiratory secretions and possibly expired air from infected pigs contained NIPV [14]; airborne dissemination of infectious material was enhanced through the violent and distinctive cough that developed in some infected pigs. The respiratory route of NIPV transmission facilitated sustained Hs I to Hs I transmission but also established pigs as a secondary reservoir or amplifying host mediating HSI to HS2 transmission of NIP V to humans and other animals [12].

6 J. E. Childs

Surveillance for infection and disease among wildlife: still a pipedream?

Every animal diagnosed as diseased has been so only after multiple interactions with humans. Locating diseased or dead wildlife is notoriously difficult and, except in rare circumstances (e.g., rabies and recent dead bird surveillance for WNV), rarely coordinated as a national surveillance activity. Most efforts to investigate wildlife HRS and prevalences of viral infection are highly focused, short-lived, and outbreak driven; these efforts rarely build the infrastructure for sustained activity. Surveillance and laboratory capacity for monitoring and diag­nosing wildlife disease (or infection) is inadequate and, at best, poorly integrated with other surveillance activities (see [9]). The hurdles and prohibitive costs of instituting any formal national wildlife disease surveillance effort indicate that targeted research initiatives remain the only viable option to investigate the complexities of zoonotic virus maintenance in wildlife. Long-term studies are essential for studying zoonotic viruses of wildlife because the dynamics of infection, transmission, and spillover are influenced by the population dynamics of the hosts, vectors, and pathogens and by habitat, environmental factors and more [24, 34]. Because of the demands on resources, not every zoonotic virus will receive attention. Although it is a difficult task, identifying priorities for collaborative study and securing national and international support for sustainable efforts should be the goal of focused studies of zoonotic diseases and disease emergence.

Priorities

Elucidating maintenance cycles, establishing the incidence And prevalence of viral infections among wildlife reservoir hosts, documenting and explaining temporal fluctuations of infection, and assessing the comparative pathogenesis of infection and disease among relevant species, are vitally important for our understanding, and potential forecasting, of the risk and consequences of zoonotic virus spillover to humans. Obtaining information of sufficient detail and quality to satisfactorily address anyone of these areas is difficult but certain zoonotic viruses or classes of virus require these efforts. I suggest and then briefly illustrate three categories of zoonotic virus deserving immediate attention; 1) zoonotic viruses of a type with an established history of pandemic emergence; 2) zoonotic viruses with a strong potential for pandemic emergence, most notably those transmitted by the respiratory route, and; 3) vector-borne zoonotic viruses with highly complex maintenance cycles, for which detailed investigations of a single system should yield results of broad significance and applicability to other systems.

Emergence is an ongoing process. Minimally, simian immunodeficiency viruses have been introduced and have established sustained inter-human trans­mission on at least eight independent occasions [11, 28]. It is nearly certain that other introductions of simian immunodeficiency viruses to human com­munities have gone locally extinct, failed to spread, or remain undetected. The extant human immunodeficiency viruses represent genetic lineages derived from

Wildlife and zoonotic viruses 7

only two of the >30 simian immunodeficiency viruses circulating among non­human primates in Africa [28]. We know little about the prevalence of simian immunodeficiency viruses among different HRS, contact rates among reservoir and secondary hosts, or the ability of different simian immunodeficiency viruses to infect and replicate in human cells. Even if access to isolated human popu­lations in West Africa were achievable, detection of novel viruses circulating in human communities would prove difficult. In addition, simian immunodeficiency viruses of the same or even different subtype, isolated from different primate species, can recombine in vivo and in test tube [13]. Recombination between simian immunodeficiency viruses within primate HR s, or possibly between human immunodeficiency virus and a simian immunodeficiency virus in co-infected humans, could result in genetic recombinants with novel phenotypes. Given our experiences with the human immunodeficiency viruses, any effort that prevents, limits, or even delays the emergence of another human-adapted simian immuno­deficiency virus would be a crowning public health achievement and should be a goal.

Other zoonotic viruses of high priority for study are those with the potential to cause pandemic human or animal disease. Consider NIPV (or the coronavirus associated with SARS) with unusual and documented capabilities to cross species boundaries. NIPV causes respiratory infection in different secondary hosts and can be transmitted by airborne routes. Although human-to-human transmission of NIPV was not documented, the pathogenesis of disease in pigs and humans appears quite similar [14]; recovery of NIPV from respiratory secretions of infected humans suggests that airborne human-to-human transmission is epidemiologically plausible [3]. Little is known about the natural history and behavioral ecology of the pteropid bats implicated as reservoir hosts for NIPV and HEN V [8] or the range of amplifying hosts susceptible to spillover. It would be premature to state that pteropid bats are the sole reservoir hosts for HENV or NIPV. A broad effort to investigate the natural history of these zoonotic viruses is not only justified but essential. As additional species of pteropid bats and other mammals will be found to host new paramyxoviruses, studies with complementary objectives in Asia and Africa are warranted. Recruiting specialists from disciplines with limited precedence for interaction (e.g., virologists and mammalogists) will be vital to these efforts.

Identification of a single or principal reservoir host for many zoonotic pathogens is difficult or impossible [12]. Consider WNV with> 160 species of birds and 37 species of mosquitoes found infected in the United States since 1999 (J. Roehrig, CDC, personal communication, 2002). Developing the matrix of outcomes between potential vertebrate HRS and vectors implicated in WNV maintenance is neither feasible nor necessary. Establishing a construct for WNV transmission that uses knowledge or estimates of the relative capacities of species to serve as competent HRS (e.g., develop high viremia, sufficient population density, attractiveness for vectors, etc.) and vectors (e.g., disseminate and transmit WNV, blood meal-host preferences, etc.) may identify broad gaps in our knowl­edge of arbovirus maintenance. As an example, increases in the population size

8 J. E. Childs

of a single species or changes in the diversity of avian species could lead to contradictory effects on epidemic spillover ofWNV [27]. Epidemic enhancement could result if changes increase the density ofWNV-infected blood meals available to competent mosquito vectors. However, not all avian species develop a WNV viremia sufficient to infect mosquito vectors [18]. If the avian fauna changes and the proportion of birds attractive to mosquitoes but variably resistant to developing West Nile virus viremia increases, then the potential for epidemics may diminish [6], even as overall bird density increases. As most quantitative models of host­pathogen interactions and population dynamics involve a single HR and a single pathogen, data accrued from WNV studies could help extend theory and provide data for model assessments.

Forecasting epizootics and extending data

Sentinel animal-based surveillance systems, such as pigs for lEV or NIPV and sentinel bird flocks for St. Louis encephalitis virus and Western equine encephalitis virus, can serve as important indicators of enzootic virus activity. However, for sentinel species to provide an early warning of impending virus spillover to humans requires distinguishing the signal of increased viral transmission (to "epizootic" levels) from the expected enzootic background; long term sampling of sentinels to collect the necessary time series data is uncommon [29,31].

Epizootics precipitated directly by environmental triggers (e.g., rainfall influ­ences mosquito breeding influences epidemic arboviral encephalitides) or indi­rectly via complex trophic cascades have been modeled to forecast virus spillover to humans. Epidemiologic models may be useful in determining the risk for human disease, even when causal chains of events are imperfectly understood [10]. Model development complements, but does not replace, the need for prospective, long­term studies to quantify how variation in vector and HR populations influence the risk of virus spillover [24].

Linking the risk of virus spillover to predictable but dynamic changes in num­bers of infected individuals in a wildlife HR population is an attractive approach, as external triggers are not required and counts of diseased individuals are easier to obtain than are population denominators. The temporal dynamics of epizootic rabies among raccoons (HR) has been used to predict the risk of rabies virus spillover to domestic cats (Hs), the principal domestic animal diagnosed with rabies in the United States [34]. Dead bird surveillance for WNV infection may provide early warning of potential spillover to humans; however, the utility of these efforts as a public health tool is still being assessed [7].

Wildlife diseases and conservation

There is a growing recognition among wildlife and conservation biologists that zoonotic diseases pose an immediate and important threat [4-6]. Cross-species transmission of exotic viruses may be the final insult that drives some endangered species to extinction. Recent epidemics of phocine distemper among harbour

Wildlife and zoonotic viruses 9

seals in the North Sea, canine distemper and rabies among African carnivores (see [15]), and Ebola disease among lowland gorillas in the Republic of the Congo [32], illustrate the devastating impact of viral diseases on certain wildlife populations.

Quantitative methods for modeling host-pathogen interactions were largely developed by ecologists interested in predation and competition. Interest in this area of research has grown dramatically and strong advocacy exists to extend these approaches to emerging diseases of wildlife and to model multi-host-pathogen systems [15]. Resources to conduct long-term, field-based studies of wildlife reservoirs of zoonotic viruses are essential, but not assured; where overlapping interests exist, scattered resources may be leveraged by collaborations among microbiologists, wildlife ecologists, and conservation biologists [32]. The study of wildlife species can provide important information on how, when, and which types of pathogens are most likely to emerge. A more anthropocentric rationale is obvious. Wildlife can serve as sentinel species for zoonotic viruses capable of spillover to humans, and prospective studies of these existing model systems provide opportunities that cannot be duplicated at any cost. If the causes of wildlife conservation and public health are promoted by such efforts, we would be doing well by doing good.

Acknowledgments

I thank the Merieux Foundation for the invitation to participate in the symposium on Emer­gence and Control of Zoonotic Encephalitis. Reviews by Drs. Charlie Calisher and Elizabeth Gordon improved this paper.

References 1. Baer GM, Neville 1, Turner GS (1996) Rabbis and rabies. Laboratorios Baer, Mexico

City 2. Childs JE, Curns AT, Dey ME, Real LA, Feinstein L, Bjornstad ON, Krebs 1W (2000)

Predicting the local dynamics of epizootic rabies among raccoons in the United States. Proc NatlAcad Sci USA 97: 13666-13671

3. Chua KB, Lam SK, Goh K1, Hooi PS, Ksiazek TG, Kamarulzaman A, Olson 1, Tan CT (2001) The presence of Nipah virus in respiratory secretions and urine of patients during an outbreak of Nipah virus encephalitis in Malaysia. 1. Infect 42: 40-43

4. Cleaveland S, Laurenson MK, Taylor LH (2001) Diseases of humans and their domestic mammals: pathogen characteristics, host range and the risk of emergence. Philos Trans R Soc Lond B BioI Sci 356: 991-999

5. Daszak P, Cunningham AA, Hyatt AD (2000) Wildlife ecology - Emerging infectious diseases of wildlife - Threats to biodiversity and human health. Science 287: 443-449

6. Dobson A, Foufopoulos 1 (200 I) Emerging infectious pathogens of wildlife. Philos Trans R Soc Lond B BioI Sci 356: 1001-1012

7. Eidson M, Kramer L, Stone W, Hagiwara Y, Schmit K (2001) Dead bird surveillance as an early warning system for West Nile virus. Emerg Infect Dis 7: 7631-7635

8. Field H, Young P, Yob 1M, Mills 1, Hall L, Mackenzie 1 (2001) The natural history of Hendra and Nipah viruses. Microbes Infect 3: 307-314

9. Friend M, McLean RG (2002) The role of native birds and other wildlife on the emergence of zoonotic diseases. In: The emergence of zoonotic diseases: understanding

10 J. E. Childs

the impact on animal and human health (Workshop Summary, ed). National Academy Press, Washington DC, pp 52-58

10. Glass GE, Yates TL, Fine JB, Shields TM, Kendall JB, Hope AG, Parmenter CA, Peters CJ, Ksiazek TG, Li CS, Patz JA, Mills IN (2002) Satellite imagery characterizes local animal reservoir populations of Sin Nombre virus in the southwestern United States. Proc Nat! Acad Sci USA 99: 16817-16822

II. Hahn BH, Shaw GM, De Cock KM, Sharp PM (2000) AIDS as a zoonosis: scientific and public health implications. Science 287: 607-614

12. Haydon DT, Cleaveland S, Taylor LH, Laurenson MK (2002) Identifying reservoirs of infection: a conceptual and practical challenge. Emerg Infect Dis 8: 1468-1473

13. Holmes EC (2001) On the origin and evolution of the human immunodeficiency virus (HIV). BioI Rev Camb Philos Soc 76: 239-254

14. Hooper P, Zaki S, Daniels P, Middleton D (2001) Comparative pathology of the diseases caused by Hendra and Nipah viruses. Microbes Infect 3: 315-322

15. Hudson PJ, RizzoliA, Grenfell BT, Heesterbeek H, DobsonAP (eds) (2002) The Ecology of wildlife diseases. Oxford University Press, Oxford

16. Institute of Medicine (1992) Emerging infections: microbial threats to health in the United States. National Academy Press, Washington DC

17. Kolar CS, Lodge DM (2001) Progress in invasion biology: predicting invaders. Trends EcolEvol 16: 199-204

18. Komar N, Langevin S, Hinten S, Nemeth N, Edwards E, Hettler D, Davis B, Bowen R, Bunning M (2003) Experimental infection of North American birds with the New York 1999 strain of West Nile virus. Emerg Infect Dis 9: 311-322

19. Ksiazek TG, Erdman D, Goldsmith CS, Zaki SR, Peret T, Emery S, Tong S, Urbani C, Comer JA, Lim W, Rollin PE, Dowell SF, Ling AE, Humphrey CD, Shieh WJ, Guarner J, Paddock CD, Rota P, Fields B, DeRisi J, Yang JY, Cox N, Hughes JM, LeDuc JW, Bellini WJ, Anderson LJ (2003) A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med 348: 1953-1966

20. Lanciotti RS, Roehrig JT, Deubel V, Smith J, Parker M, Steele K, Crise B, Volpe KE, Crabtree MB, Scherret JH, Hall RA, Mackenzie JS, Cropp CB, Panigrahy B, Ostlund E, Schmitt B, Malkinson M, Banet C, Weissman J, Komar N, Savage HM, Stone W, McNamara T, Gubler DJ (1999) Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States. Science 286: 2333-2337

21. Linthicum KJ, An yambaA, Tucker CJ, Kelley PW, Myers MF, Peters CJ (1999) Climate and satellite indicators to forecast Rift Valley fever epidemics in Kenya. Science 285: 397--400

22. Mackenzie JS, Chua KB, Daniels PW, Eaton BT, Field HE, Hall RA, Halpin K, Johansen CA, Kirkland PD, Lam SK, McMinn P, Nisbet DJ, Paru R, Pyke AT, Ritchie SA, Siba P, Smith DW, Smith GA, van den Hurk AF, Wang LF, Williams DT (2001) Emerging viral diseases of Southeast Asia and the Western Pacific. Emerg Infect Dis 7: 497-504

23. Malkinson M, Banet C, Weisman Y, Pokamunski S, King R, Drouet MT, Deubel V (2002) Introduction of West Nile virus in the Middle East by migrating white storks. Emerg Infect Dis 8: 392-397

24. Mills IN, Childs JE (1998) Ecological studies of rodent reservoirs: their relevance for human health. Emerg Infect Dis 4: 529-537

25. Mims CA (1995) Virology research and virulent human pandemics. Epidemiol Infect 115: 377-386

26. Morse SS (1995) Factors in the emergence of infectious diseases. Emerg Infect Dis I: 7-15

Wildlife and zoonotic viruses 11

27. Ostfeld RS, Keesing F (2000) Biodiversity and disease risk: the case of Lyme disease. Conserv BioI 14: 722-728

28. Peeters M, Courgnaud V, Abela B, Auzel P, Pourrut X, Bibollet-Ruche F, Loul S, Liegeois F, Butel C, Koulagna D, Mpoudi-Ngole E, Shaw GM, Hahn BH, Delaporte E (2002) Risk to human health from a plethora of simian immunodeficiency viruses in primate bushmeat. Emerg Infect Dis 8: 451--457

29. Reeves WC (1990) Epidemiology and control of mosquito-borne arboviruses in California. California Mosquito and Vector Control Association, Inc., Sacramento, 1943-1987

30. Schrag SJ, Wiener P (1995) Emerging infectious disease: what are the relative roles of ecology and evolution? Trends Ecol Evol 10: 319-324

31. Shaman J, Day JF, Stieglitz M (2002) Drought-induced amplification of Saint Louis encephalitis virus, Florida. Emerg Infect Dis 8: 575-580

32. Walsh PD, Abernethy KA, Bermejo M, Beyers R, De Wachter P, Akou ME, Huijbregts B, Mambounga 01, Toham AK, Kilbourn AM, Lahm SA, Latour S, Maisels F, Mbina C, Mihindou Y, Obiang SN, Effa EN, Starkey MP, Telfer P, Thibault M, Tutin CE, White LJ, Wilkie DS (2003) Catastrophic ape decline in Western equatorial Africa. Nature 422: 611-614

33. Wang L, Harcourt BH, Yu M, Tamin A, Rota PA, Bellini WJ, Eaton BT (2001) Molecular biology of Hendra and Nipah viruses. Microbes Infect 3: 279-287

34. Gordon ER, Curns AT, Krebs JW, Rupprecht CE, Real LA, Childs JE. Temporal dynamics of rabies in a wildlife host and the risk of interspecific transmission. Epidemiol Infect (in press).

Author's address: James E. Childs, Viral and Rickettsial Zoonoses Branch, National Center for Infectious Diseases, Centers for Disease Control and Prevention, MS-G 13, 1600 Clifton Road, Atlanta, GA 30333, U.S.A.; e-mail: jameschilds@comcast.net