Artois, M.

Boadella, M.

de la Fuente, J.

Delahay, R.

Drosten, C.

Estrada-Peña, A.

Gortazar, C.

Kuiken, T.

Martínez-Lopez, B.

Medley, G.

Menge, C.

Ostfeld, R.

Peterson, T.

Reperant, L.A.

Ruiz-Fons, F.

Schultsz, C.

Serra-C

VerCauteren, K.C.

PLoS Pathogens

Jukuri

PearlsCrossing the Interspecies Barrier: Opening the Door toZoonotic PathogensChristian Gortazar1*, Leslie A. Reperant2, Thijs Kuiken2, Jose´ de la Fuente1,3, Mariana Boadella1,Beatriz Martı´nez-Lopez4, Francisco Ruiz-Fons1, Agustin Estrada-Pen˜a5, Christian Drosten6,Graham Medley7, Richard Ostfeld8, Townsend Peterson9, Kurt C. VerCauteren10, Christian Menge11,Marc Artois12, Constance Schultsz13, Richard Delahay14, Jordi Serra-Cobo15, Robert Poulin16,Frederic Keck17, Alonso A. Aguirre18, Heikki Henttonen19, Andrew P. Dobson20, Susan Kutz21,Juan Lubroth22, Atle Mysterud231 SaBio IREC (CSIC-Universidad de Castilla-La Mancha), Ciudad Real, Spain, 2 Department of Viroscience, Erasmus University Medical Centre, Rotterdam, Netherlands,3 Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, Oklahoma, United States of America, 4 Center forAnimal Disease Modeling and Surveillance, Department of Medicine and Epidemiology, University of California, Davis, Davis, California, United States of America, 5 Facultyof Veterinary Medicine, Department of Animal Pathology, University of Zaragoza, Zaragoza, Spain, 6Universita¨ts-Klinikum Bonn und Medizinische Fakulta¨t, Bonn,Germany, 7 School of life Sciences, University of Warwick, Coventry, United Kingdom, 8Harvard Center for the Environment, Harvard University, Cambridge,Massachusetts, United States of America, 9 Biodiversity Institute University of Kansas, Lawrence, Kansas, United States of America, 10USDA/APHIS/WS/National WildlifeResearch Center, Fort Collins, Colorado, United States of America, 11 Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Jena, Germany, 12 Universite´de Lyon, Campus Ve´te´rinaire de Lyon, VetAgro Sup, Marcy L’E´toile, France, 13 Academic Medical Centre, University of Amsterdam, Amsterdam Institute for Global Healthand Development, Amsterdam, Netherlands, 14National Wildlife Management Centre, Animal Health and Veterinary Laboratories Agency, Nympsfield, Stonehouse,Gloucestershire, United Kingdom, 15 IRBIO and Departement de Biologia Animal, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain, 16 Department ofZoology, University of Otago, Dunedin, New Zealand, 17 Centre National de la Recherche Scientifique, Laboratoire D’anthropologie Sociale, Paris, France, 18 Departmentof Environmental Science and Policy, George Mason University, Fairfax, Virginia, United States of America, 19 Vantaa Unit, Finnish Forest Research Institute, Vantaa,Finland, 20Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America, 21 Department of Ecosystem andPublic Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada, 22Animal Production and Health Division, Food and Agriculture Organization of theUnited Nations–Headquarters, Rome, Italy, 23 Centre for Ecological and Evolutionary Synthesis (CEES), Department of Biosciences, University of Oslo, Oslo, NorwayZoonotic PathogensThe number of pathogens known to infect humans is everincreasing. Whether such increase reflects improved surveillanceand detection or actual emergence of novel pathogens is unclear.Nonetheless, infectious diseases are the second leading cause ofhuman mortality and disability-adjusted life years lost worldwide[1,2]. On average, three to four new pathogen species are detectedin the human population every year [3]. Most of these emergingpathogens originate from nonhuman animal species.Zoonotic pathogens represent approximately 60% of all knownpathogens able to infect humans [4]. Their occurrence in humansrelies on the human-animal interface, defined as the continuum ofcontacts between humans and animals, their environments, or theirproducts. The human-animal interface has existed since the firstfootsteps of the human species and its hominin ancestors 6–7 millionyears ago, promoting the prehistoric emergence of now well-established human pathogens [5]. These presumably includepathogens with roles in the origin of chronic diseases, such as humanT-lymphotropic viruses and Helicobacter pylori, as well as pathogenscausing major crowd diseases, such as the smallpox and measlesviruses and Bordetella pertussis [5,6]. Since prehistory, the human-animal interface has continued to evolve and expand, ever allowingnew pathogens to access the human host and cross species barriers [5].Species BarriersThe suitability of any species to act as a host to a particularpathogen varies due to both host species– and pathogen-dependent factors, which define the species barriers. The speciesbarriers separating nonhuman animal species from humans andthus of concern for zoonotic pathogens are the focus of this paper.However, the proposed conceptual framework is applicable to anyhost-pathogen system.The species barriers separating nonhuman animal species fromhumans represent a major hurdle for effective exposure to,infection by, and subsequent spread of zoonotic pathogens amonghumans [7]. Accordingly, these species barriers can be divided intothree largely complementary sets. First, the interspecies barrierdetermines the nature and level of human exposure to zoonoticpathogens. Second, the intrahuman barrier determines the abilityof zoonotic pathogens to productively infect a human host andeffectively cope with the immune response. Third, the interhumanbarrier determines the ability of zoonotic pathogens to efficientlytransmit among humans, causing outbreaks, epidemics, orpandemics. Zoonotic pathogens may cross, more or less efficiently,one or more of these sets of barriers. Only pathogens that cross allbarriers have the potential to sustainably establish in the humanpopulation.Identifying the factors allowing pathogens to cross each of thesethree sets of barriers is essential to mitigate burdens of known andfuture emerging zoonotic pathogens. The interspecies barrier, byCitation: Gortazar C, Reperant LA, Kuiken T, de la Fuente J, Boadella M, etal. (2014) Crossing the Interspecies Barrier: Opening the Door to ZoonoticPathogens. PLoS Pathog 10(6): e1004129. doi:10.1371/journal.ppat.1004129Editor: Vincent Racaniello, Columbia University, United States of AmericaPublished June 19, 2014This is an open-access article, free of all copyright, and may be freely reproduced,distributed, transmitted, modified, built upon, or otherwise used by anyone forany lawful purpose. The work is made available under the Creative Commons CC0public domain dedication.Funding: This research was funded by EU FP7 grant ANTIGONE (#278976). Thefunders had no role in study design, data collection and analysis, decision topublish, or preparation of the manuscript.Competing Interests: The authors have declared that no competing interestsexist.* E-mail: Christian.Gortazar@uclm.esPLOS Pathogens | www.plospathogens.org 1 June 2014 | Volume 10 | Issue 6 | e1004129its nature, involves ecological processes driving animal and humanpopulation dynamics and interspecies contact. Prior attempts todefine these factors or drivers started as early as 1992 [8]. Recentcontributions in this field underlined the importance of landscapechange and ecological alteration (e.g., [9–11]). Here, we build onthese earlier studies to focus on identifying the factors affecting theinterspecies barrier from a more holistic perspective, with the aimof developing a simple framework that classifies factors into alimited number of mutually exclusive categories acting at distinctspatial and temporal scales.Conceptual Framework for Pathogen Emergenceat the Interspecies BarrierThe emergence of zoonotic pathogens in humans is dependenton interactions between humans and infected animal reservoirand/or vector hosts or their environment (Figure 1, center). Theextent of such interactions is influenced by the prevalence ofzoonotic pathogens in the animal reservoir or vector populations,which is in turn influenced by these populations’ health andimmune status. In addition, the population dynamics of humans,animal reservoirs, and vectors drive ecological processes thatgovern pathogen abundance and spread, both within and amongspecies [12]. Increased exposure of humans to animal pathogenscan result from changes in the dynamics of any of thesepopulations (Figure 1, inner circle). These changes can be dividedinto three categories: first, increased interspecies contact betweenhumans and the animal reservoir and/or vector; second,population growth or aggregation of humans, animal reservoir,and/or vector; and third, their geographic range expansion, atleast where this expansion involves overlapping ranges. Changes inone aspect of human, animal reservoir, or vector populationdynamics may affect another; for example, population growth mayaccompany range expansion.Factors influencing these changes in human, animal reservoir,and vector population dynamics may themselves be divided intotwo sets of drivers, acting at distinct scales. First, ‘‘proximatedrivers’’ occurring at the local landscape scale are directdeterminants of changes in human, animal reservoir, and vectorpopulation dynamics (Figure 1, middle circle; Table 1). Thesedrivers may include habitat suitability, food and water resourceavailability, and short- or long-distance movements. The extent toFigure 1. Framework for the classification of drivers of human exposure to animal pathogens (interspecies barrier). See text for moredetails.doi:10.1371/journal.ppat.1004129.g001PLOS Pathogens | www.plospathogens.org 2 June 2014 | Volume 10 | Issue 6 | e1004129which changes in these proximate drivers affect human, animalreservoir, and vector population dynamics depends greatly on theecology of the species under consideration. For example, changesin habitat may favor generalist species but may drive specialistspecies to local extinction.Second, ‘‘ultimate drivers’’ occurring at broader (regional orglobal) geographic scales temporally precede and govern changesin proximate drivers (Figure 1, outer circle; Table 1). These driversinclude climate, land use, and animal management. Changes inthese ultimate drivers may be either anthropogenic (humancaused) or ‘‘natural.’’ They can promote changes in one or moreproximate drivers. For example, changes in land use may affectboth habitat suitability and availability of food and water.Together, the above framework allows the proposed underlyingfactors affecting the interspecies barrier to be categorizedsystematically (Figure 2).Gaps in Current Knowledge of the Ecology ofZoonotic PathogensThe proposed framework helps identify essential gaps in ourunderstanding of the chain of emergence of zoonotic pathogens inhumans and, in particular, of ecological processes underlyingcrossing of the interspecies barrier. Major gaps include character-ization of the relationships between environmental conditions,especially climate and weather, and host and/or vector populationdynamics, as well as exploration of pathogen survival andpropagation in the environment. Recent studies have aimed ataddressing such issues using novel approaches [13] and areessential in order to detect and predict associations betweendrivers such as climate change or weather variability and pathogenemergence [14,15]. The current focus in ecology addressesprimarily single host-pathogen systems and needs to be expandedto a multihost, multipathogen perspective. Interactions betweenhost, vector, and pathogenic and nonpathogenic infectious agentslikely play important roles in the dynamics of zoonotic pathogensat the human-animal interface [14]. Lastly, systematic assessmentof actual human exposure to zoonotic pathogens, e.g., by serology,is lacking, calling for a more holistic approach to understandingthe complete chain of emergence. Most evidence for the role ofanthropogenic changes, e.g., encroachment into natural habitats,on zoonotic pathogen emergence is anecdotal or indirect andgenerally biased towards developed countries.Future PerspectivesThe identification of a limited number of mutually exclusivedrivers of zoonotic pathogen emergence and of current knowledgegaps is essential to improve risk assessment and preventionmeasures. The links between pathogen emergence in humans andtheir underlying factors are typically speculative and associative andusually only account for a short section of the chain of emergence.Overall, knowledge of causal relationships between changes inpopulation dynamics or interspecies contact, on the one hand, andpathogen emergence in humans, on the other, is fragmentary andincomplete at best. Existing studies in this area generally are limitedin scope and typically lack quantitative assessment of humanexposure to zoonotic pathogens at the human-animal interface.The above proposed framework helps in understanding thecommon mechanisms behind disease emergence by linkingpathogen emergence in humans to distinct and well-definedTable 1. Drivers for overcoming the interspecies barrier.Ultimate Drivers Proximate DriversClimate variability and change Movement/migrationEl Nin˜o-Southern Oscillation and North Atlantic Oscillation Displacement (e.g., due to flooding or habitat destruction)Warming; season extension; extremes in heat and cold Inhibited migration (e.g., due to fencing)Flooding Human urban migrationDrought Habitat changeLand-use change Improved habitat (e.g., for invertebrate vectors due to extension of breeding season)Deforestation Loss of natural habitat (e.g., for bats due to deforestation)Pasture to cropland Habitat fragmentationIntensification of crop production Food and water changeReforestation and agricultural abandonment Increased food (e.g., for waterbirds due to intensification of crop production or for deer due towinter feeding)Urbanisation Changed food (e.g., for dairy cattle due to intensification of livestock production or for humansdue to intensification of livestock and crop productions as well as changes in food manufacturingand consumption practices)Animal-management change Water contaminationFree-livingChanges in harvesting/cullingConservation measures and translocationsFeedingFencing of natural habitatDomesticIntensification of livestock productionIncreasing trade of animals and animal productsdoi:10.1371/journal.ppat.1004129.t001PLOS Pathogens | www.plospathogens.org 3 June 2014 | Volume 10 | Issue 6 | e1004129proximate and ultimate drivers. Hence, it may be used to furtheridentify and quantify associations, causal relationships, and risksbetween ecological changes and pathogen emergence. In the fullsense of the One Health concept, it can serve to help optimizeefforts to manage disease emergence and spread in the interests ofhumans, food safety, and biodiversity.References1. Fauci AS (2001) Infectious diseases: considerations for the 21st century. ClinInfect Dis 2001 32: 675–685.2. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, et al. (2012) Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet380: 2197–2223.3. Woolhouse M, Scott F, Hudson Z, Howey R, Chase-Topping M (2012) Humanviruses: discovery and emergence. Philos Trans R Soc Lond B Biol Sci 367:2864–2871.4. Taylor LH, Latham SM, Woolhouse ME (2001) Risk factors for human diseaseemergence. Philos Trans R Soc Lond B Biol Sci 356: 983–989.5. 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(A)Emergence of Sin Nombre virus in the Four Corners area of the United States in 1993 was attributed to population growth of the rodent reservoir(Peromyscus maniculatus) following increases in food resources (mast) associated with El Nin˜o-Southern Oscillation events [16]. (B) Emergence ofBorrelia burgdorferi in the eastern US in 1974 was attributed to population growth and range expansion of white-tailed-deer (Odocoileus virginianus)and black-legged-tick (Ixodes scapularis) vector populations following increase in suitable habitat due to reforestation and management encouraginghigh deer densities [17]. (C) Emergence of Ebola virus in the Democratic Republic of Congo (formerly Zaire) in 1976 was attributed to increases ininterspecies contact between humans and primates following increases in bushmeat hunting and encroachment into undisturbed habitats [18]. (D)Emergence of enteric pathogenic Escherichia coli at the human-animal interface was attributed to increased direct and indirect human-animal contactfollowing changes in the food chain and in water quality, often due to the intensification of livestock production [19].doi:10.1371/journal.ppat.1004129.g002PLOS Pathogens | www.plospathogens.org 4 June 2014 | Volume 10 | Issue 6 | e10041299. Patz JA, Daszak P, Tabor GM, Aguirre AA, Pearl M, et al. (2004) Unhealthylandscapes: Policy recommendations on land use change and infectious diseaseemergence. Environ Health Perspect 112: 1092–1098.10. Woolhouse M, Gaunt E (2007) Ecological origins of novel human pathogens.Crit Rev Microbiol 33: 231–242.11. Myers SS, Gaffikin L, Golden CD, Ostfeld RS, Redford KH, et al. (2013) Humanhealth impacts of ecosystem alteration. Proc Natl Acad SciU SA 110: 18753–18760.12. Reperant LA (2010) Applying the theory of island biogeography to emergingpathogens: toward predicting the sources of future emerging zoonotic andvector-borne diseases. Vector Borne Zoonotic Dis 10: 105–110.13. Molnar PK, Kutz SJ, Hoar BM, Dobson AP (2013) Metabolic approaches tounderstanding climate change impacts on seasonal host-macroparasite dynam-ics. Ecol Lett 16: 9–21.14. Altizer S, Ostfeld RS, Johnson PT, Kutz S, Harvell CD (2013) Climate change andinfectious diseases: from evidence to a predictive framework. Science 341: 514–519.15. Semenza JC, Menne B (2009) Climate change and infectious diseases in Europe.Lancet Infect Dis 9: 365–375.16. Engelthaler DM, Mosley DG, Cheek JE, Levy CE, Komatsu KK, et al. (1999)Climatic and environmental patterns associated with hantavirus pulmonarysyndrome, Four Corners region, United States. Emerg Infect Dis 5: 87–94.17. Barbour AG, Fish D (1993) The biological and social phenomenon of Lymedisease. Science 260: 1610–1616.18. Wolfe ND, Daszak P, Kilpatrick AM, Burke DS (2005) Bushmeat hunting,deforestation, and prediction of zoonoses emergence. Emerg Infect Dis 11:1822–1827.19. Beutin L, Hammerl JA, Reetz J, Strauch E (2013) Shiga toxin-producingEscherichia coli strains from cattle as a source of the Stx2a bacteriophagespresent in enteroaggregative Escherichia coli O104:H4 strains. Int J MedMicrobiol 303: 595–602.PLOS Pathogens | www.plospathogens.org 5 June 2014 | Volume 10 | Issue 6 | e1004129

Crossing the Interspecies Barrier: Opening the Door to Zoonotic Pathogens.

Crossing the Interspecies Barrier: Opening the Door to Zoonotic Pathogens.

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