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Origins of major human infectious diseases

Origins of major human infectious diseases Vol 447j17 May 2007jdoi:10.1038/nature05775 REVIEWS 1 2 3 Nathan D. Wolfe , Claire Panosian Dunavan & Jared Diamond Many of the major human infectious diseases, including some now confined to humans and absent from animals, are ‘new’ ones that arose only after the origins of agriculture. Where did they come from? Why are they overwhelmingly of Old World origins? Here we show that answers to these questions are different for tropical and temperate diseases; for instance, in the relative importance of domestic animals and wild primates as sources. We identify five intermediate stages through which a pathogen exclusively infecting animals may become transformed into a pathogen exclusively infecting humans. We propose an initiative to resolve disputed origins of major diseases, and a global early warning system to monitor pathogens infecting individuals exposed to wild animals. uman hunter/gatherer populations currently suffer, and unicellular microbial pathogens. We exclude macroparasites (in presumably have suffered for millions of years, from infec- the sense of ref. 7), as well as normally benign commensals that cause tious diseases similar or identical to diseases of other wild serious illness only in weakened hosts. The extensive Supplementary H primate populations. However, the most important infec- Information provides details and references on our 25 diseases, tious diseases of modern food-producing human populations also robustness tests of our conclusions, factors affecting transitions include diseases that could have emerged only within the past 11,000 between disease stages, and modern practices altering the risk of 1,2 years, following the rise of agriculture . We infer this because, as emergence of new diseases. discussed below, these diseases can only be sustained in large dense Evolutionary stages human populations that did not exist anywhere in the world before agriculture. What were the sources of our major infectious diseases, Box 1 delineates five intergrading stages (Fig. 1) through which a including these ‘new’ ones? Why do so many animal pathogens, pathogen exclusively infecting animals (Stage 1) may become trans- including virulent viruses like Ebola and Marburg, periodically formed into a pathogen exclusively infecting humans (Stage 5). infect human hosts but then fail to establish themselves in human Supplementary Table S1 assigns each of the 25 major diseases dis- populations? cussed (Supplementary Note S1) to one of these five stages. A tentative earlier formulation noted that major infectious dis- A large literature discusses the conditions required for a Stage 5 2,7 eases of temperate zones seem to have arisen overwhelmingly in the epidemic to persist . Briefly, if the disease infects only humans and Old World (Africa, Asia and Europe), often from diseases of Old lacks an animal or environmental reservoir, each infected human World domestic animals. Hence one goal of this article is to re- introduced into a large population of susceptible individuals must appraise that conclusion in the light of studies of the past decade. on average give rise during his/her contagious lifespan to an infection Another goal is to extend the analysis to origins of tropical diseases . in at least one other individual. Persistence depends on factors such We shall show that they also arose mainly in the Old World, but for as the duration of a host’s infectivity; the rate of infection of new different reasons, and mostly not from diseases of domestic animals. hosts; rate of development of host protective immunity; and host These results provide a framework for addressing unanswered population density, size and structure permitting the pathogen’s questions about the evolution of human infectious diseases—ques- regional persistence despite temporary local extinctions. tions not only of practical importance to physicians, and to all the rest Less well understood are two of the critical transitions between of us as potential victims, but also of intellectual interest to historians stages, discussed in Box 2. One is the transition from Stage 1 to Stage and evolutionary biologists. Historians increasingly recognize that 2, when a pathogen initially confined to animals first infects humans. infectious diseases have had major effects on the course of history; The other is the transition from Stage 2 to Stages 3 and 4 (see also for example, on the European conquest of Native Americans and Supplementary Note S2), when a pathogen of animal origin that is Pacific Islanders, the inability of Europeans to conquer the Old nevertheless transmissible to humans evolves the ability to sustain World tropics for many centuries, the failure of Napoleon’s invasion many cycles of human-to-human transmission, rather than just a few of Russia, and the failure of the French attempt to complete con- cycles before the outbreak dies out (as seen in modern Ebola out- 4–6 struction of a Panama Canal . Evolutionary biologists realize that breaks). infectious diseases, as a leading cause of human morbidity and mor- 2,7 tality, have exerted important selective forces on our genomes . Database and conclusions We begin by defining five stages in the evolutionary transforma- Database. Supplementary Table S1 lists 10 characteristics for each tion of an animal pathogen into a specialized pathogen of humans, of 25 important ‘temperate’ (15) and ‘tropical’ (10) diseases (see and by considering why so many pathogens fail to make the trans- Supplementary Note S3 for details of this distinction). Our aim ition from one stage to the next. We then assemble a database of 15 was to select well-defined diseases causing the highest mortality temperate and 10 tropical diseases of high evolutionary and/or his- and/or morbidity and hence of the highest historical and evolution- torical impact, and we compare their characteristics and origins. Our ary significance (see Supplementary Note S1 for details of our selec- concluding section lays out some unresolved questions and suggests tion criteria). Of the 25 diseases, we selected 17 because they are the two expanded research priorities. We restrict our discussion to ones assessed by ref. 8 as imposing the heaviest world burdens today 1 2 Department of Epidemiology, School of Public Health, University of California, Los Angeles 90095-1772, USA. Division of Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles 90095-1688, USA. Departments of Geography and of Environmental Health Sciences, University of California, Los Angeles 90095-1524, USA. © 2007Nature PublishingGroup REVIEWS NATUREjVol 447j17 May 2007 Are our conclusions robust to variations in these selection criteria? Box 1 j Five stages leading to endemic human diseases For about a dozen diseases with the highest modern or historical We delineate five stages in the transformation of an animal pathogen burdens (for example, AIDS, malaria, plague, smallpox), there can into a specialized pathogen of humans (Fig. 1). There is no inevitable be little doubt that they must be included, but one could debate some progression of microbes from Stage 1 to Stage 5: at each stage many of the next choices. Hence we drew up three alternative sets of dis- microbes remain stuck, and the agents of nearly half of the 25 eases sharing a first list of 16 indisputable major diseases but differing important diseases we selected for analysis (Supplementary Table S1) in the next choices, and we performed all 10 analyses described below have not reached Stage 5. Stage 1. A microbe that is present in animals but that has not on all three sets. It turned out that, with one minor exception, the been detected in humans under natural conditions (that is, three sets yielded qualitatively the same conclusions for all 10 analyses, excluding modern technologies that can inadvertently transfer although differing in their levels of statistical significance (see Sup- microbes, such as blood transfusion, organ transplants, or plementary Note S4). Thus, our conclusions do seem to be robust. hypodermic needles). Examples: most malarial plasmodia, which Temperate/tropical differences. Comparisons of these temperate tend to be specific to one host species or to a closely related and tropical diseases yield the following conclusions: group of host species. A higher proportion of the diseases is transmitted by insect . Stage 2. A pathogen of animals that, under natural conditions, vectors in the tropics (8/10) than in the temperate zones (2/ has been transmitted from animals to humans (‘primary infection’) but has not been transmitted between humans 15) (P, 0.005, x -test, degrees of freedom, d.f.5 1). This dif- (‘secondary infection’). Examples: anthrax and tularemia bacilli, ference may be partly related to the seasonal cessations or and Nipah, rabies and West Nile viruses. declines of temperate insect activity. Stage 3. Animal pathogens that can undergo only a few cycles of A higher proportion (P5 0.009) of the diseases conveys long- secondary transmission between humans, so that occasional lasting immunity (11/15) in the temperate zones than in the human outbreaks triggered by a primary infection soon die out. tropics (2/10). Examples: Ebola, Marburg and monkeypox viruses. . Animal reservoirs are more frequent (P, 0.005) in the tropics . Stage 4. A disease that exists in animals, and that has a natural (8/10) than in the temperate zones (3/15). The difference is in (sylvatic) cycle of infecting humans by primary transmission the reverse direction (P5 0.1, NS, not significant) for envir- from the animal host, but that also undergoes long sequences of secondary transmission between humans without the onmental reservoirs (1/10 versus 6/15), but those envir- involvement of animal hosts. We arbitrarily divide Stage 4 into onmental reservoirs that do exist are generally not of major three substages distinguished by the relative importance of significance except for soil bearing tetanus spores. primary and secondary transmission: Most of the temperate diseases (12/15) are acute rather than Stage 4a. Sylvatic cycle much more important than direct slow, chronic, or latent: the patient either dies or recovers human-to-human spread. Examples: Chagas’ disease and (more within one to several weeks. Fewer (P5 0.01) of the tropical frequent secondary transmission approaching Stage 4b) yellow diseases are acute: 3/10 last for one or two weeks, 3/10 last for fever. weeks to months or years, and 4/10 last for many months to Stage 4b. Both sylvatic and direct transmission are important. decades. Example: dengue fever in forested areas of West Africa and Southeast Asia. A somewhat higher proportion of the diseases (P5 0.08, NS) Stage 4c. The greatest spread is between humans. Examples: belongs to Stage 5 (strictly confined to humans) in the tem- influenza A, cholera, typhus and West African sleeping sickness. perate zones (10/15 or 11/15) than in the tropics (3/10). The Stage 5. A pathogen exclusive to humans. Examples: the agents paucity of Stage 2 and Stage 3 diseases (a total of only 5 such causing falciparum malaria, measles, mumps, rubella, smallpox diseases) on our list of 25 major human diseases is noteworthy, and syphilis. In principle, these pathogens could have become because some Stage 2 and Stage 3 pathogens (such as anthrax confined to humans in either of two ways: an ancestral pathogen and Ebola) are notoriously virulent, and because theoretical already present in the common ancestor of chimpanzees and reasons are often advanced (but also denied) as to why Stage 5 humans could have co-speciated long ago, when the chimpanzee microbes with long histories of adaptation to humans should and human lineages diverged around five million years ago; or else an animal pathogen could have colonized humans more tend to evolve low morbidity and mortality and not cause recently and evolved into a specialized human pathogen. Co- major diseases. We discuss explanations for this outcome in speciation accounts well for the distribution of simian foamy Supplementary Note S5. viruses of non-human primates, which are lacking and Most (10/15) of the temperate diseases, but none of the tropical presumably lost in humans: each virus is restricted to one diseases (P, 0.005), are so-called ‘crowd epidemic diseases’ (aster- primate species, but related viruses occur in related primate isked in Supplementary Table S1), defined as ones occurring locally species . While both interpretations are still debated for as a brief epidemic and capable of persisting regionally only in large falciparum malaria, the latter interpretation of recent origins is human populations. This difference is an immediate consequence of widely preferred for most other human Stage 5 diseases of the differences enumerated in the preceding five paragraphs. If a Supplementary Table S1. disease is acute, efficiently transmitted, and quickly leaves its victim either dead or else recovering and immune to re-infection, the epi- (they have the highest disability-adjusted life years (DALY) scores). demic soon exhausts the local pool of susceptible potential victims. If Of the 17 diseases, 8 are temperate (hepatitis B, influenza A, measles, in addition the disease is confined to humans and lacks significant pertussis, rotavirus A, syphilis, tetanus and tuberculosis), and 9 are animal and environmental reservoirs, depletion of the local pool of tropical (acquired immune deficiency syndrome (AIDS), Chagas’ potential victims in a small, sparse human population results in local disease, cholera, dengue haemorrhagic fever, East and West African termination of the epidemic. If, however, the human population is sleeping sicknesses, falciparum and vivax malarias, and visceral leish- large and dense, the disease can persist by spreading to infect people maniasis). We selected eight others (temperate diphtheria, mumps, in adjacent areas, and then returning to the original area in a later plague, rubella, smallpox, typhoid and typhus, plus tropical yellow year, when births and growth have regenerated a new crop of prev- fever) because they imposed heavy burdens in the past, although iously unexposed non-immune potential victims. Empirical epide- modern medicine and public health have either eradicated them miological studies of disease persistence or disappearance in isolated (smallpox) or reduced their burden. Except for AIDS, dengue fever, human populations of various sizes have yielded estimates of the and cholera, which have spread and attained global impact in modern population required to sustain a crowd disease: at least several hun- 2,7 times, most of these 25 diseases have been important for more than dred thousand people in the cases of measles, rubella and pertussis . two centuries. But human populations of that size did not exist anywhere in the © 2007Nature PublishingGroup NATUREjVol 447j17 May 2007 REVIEWS Transmission Stage to humans Stage 5: exclusive Only from human agent humans Stage 4: From animals long outbreak or (many cycles) humans Stage 3: From animals limited or (few cycles) outbreak humans Stage 2: primary Only from animals infection Stage 1: agent only None in animals Rabies Ebola Dengue HIV-1 M Figure 1 | Illustration of the five stages through which pathogens of process, ranging from rabies (still acquired only from animals) to HIV-1 animals evolve to cause diseases confined to humans. (See Box 1 for (now acquired only from humans). details.) The four agents depicted have reached different stages in the world until the steep rise in human numbers that began around Supplementary Note S7). Why do temperate and tropical human 1,9 11,000 years ago with the development of agriculture . Hence the diseases differ so markedly in their animal origins? Many (4/10) crowd epidemic diseases of the temperate zones must have evolved tropical diseases (AIDS, dengue fever, vivax malaria, yellow fever) since then. but only 1/15 temperate diseases (hepatitis B) have wild non-human Of course, this does not mean that human hunter/gatherer com- primate origins (P5 0.04). This is because although non-human munities lacked infectious diseases. Instead, like the sparse popula- primates are the animals most closely related to humans and hence tions of our primate relatives, they suffered from infectious diseases pose the weakest species barriers to pathogen transfer, the vast major- with characteristics permitting them to persist in small populations, ity of primate species is tropical rather than temperate. Conversely, unlike crowd epidemic diseases. Those characteristics include: occur- few tropical but many temperate diseases arose from domestic ani- rence in animal reservoirs as well as in humans (such as yellow fever); mals, and this is because domestic animals live mainly in the tem- perate zones, and their concentration there was formerly even more incomplete and/or non-lasting immunity, enabling recovered patients to remain in the pool of potential victims (such as malaria); lop-sided (see Supplementary Note S8). and a slow or chronic course, enabling individual patients to con- A final noteworthy point about animal-derived human pathogens tinue to infect new victims over years, rather than for just a week or is that virtually all arose from pathogens of other warm-blooded two (such as Chagas’ disease). vertebrates, primarily mammals plus in two cases (influenza A and Pathogen origins. (See details for each disease in Supplementary ultimately falciparum malaria) birds. This comes as no surprise, con- sidering the species barrier to pathogen transfer posed by phylogen- Note S10). Current information suggests that 8 of the 15 temperate diseases probably or possibly reached humans from domestic ani- etic distance (Box 2). An expression of this barrier is that primates mals (diphtheria, influenza A, measles, mumps, pertussis, rotavirus, constitute only 0.5% of all vertebrate species but have contributed smallpox, tuberculosis); three more probably reached us from apes about 20% of our major human diseases. Expressed in another way, (hepatitis B) or rodents (plague, typhus); and the other four (rubella, the number of major human diseases contributed, divided by the syphilis, tetanus, typhoid) came from still-unknown sources (see number of animal species in the taxonomic group contributing those Supplementary Note S6). Thus, the rise of agriculture starting diseases, is approximately 0.2 for apes, 0.017 for non-human pri- 11,000 years ago played multiple roles in the evolution of animal mates other than apes, 0.003 for mammals other than primates, 1,4,10 pathogens into human pathogens . Those roles included both 0.00006 for vertebrates other than mammals, and either 0 or else generation of the large human populations necessary for the evolu- 0.000003 (if cholera really came from aquatic invertebrates) for ani- tion and persistence of human crowd diseases, and generation of mals other than vertebrates (see Supplementary Note S9). large populations of domestic animals, with which farmers came into Geographic origins. To an overwhelming degree, the 25 major much closer and more frequent contact than hunter/gatherers had human pathogens analysed here originated in the Old World. That with wild animals. Moreover, as illustrated by influenza A, these proved to be of great historical importance, because it facilitated domestic animal herds served as efficient conduits for pathogen the European conquest of the New World (the Americas). Far more transfers from wild animals to humans, and in the process may have Native Americans resisting European colonists died of newly intro- evolved specialized crowd diseases of their own. duced Old World diseases than of sword and bullet wounds. Those It is interesting that fewer tropical than temperate pathogens ori- invisible agents of New World conquest were Old World microbes to ginated from domestic animals: not more than three of the ten trop- which Europeans had both some acquired immunity based on indi- ical diseases of Supplementary Table S1, and possibly none (see vidual exposure and some genetic resistance based on population © 2007Nature PublishingGroup REVIEWS NATUREjVol 447j17 May 2007 exposure over time, but to which previously unexposed Native 1,4–6 American populations had no immunity or resistance . In con- Box 2 Transitions between stages trast, no comparably devastating diseases awaited Europeans in the Transition from Stage 1 to Stage 2. Most animal pathogens are not New World, which proved to be a relatively healthy environment for transmitted tohumans, that is, they do not even pass from Stage 1 toStage Europeans until yellow fever and malaria of Old World origins 2. This problem of cross-species infection has been discussed 20–23 arrived . previously . Briefly, the probability-per-unit-time (p) of infection of an individual of a new (that is, new recipient) host species increases with the Why was pathogen exchange between Old and New Worlds so abundance of theexisting (that is, existingdonor) host, with thefraction of unequal? Of the 25 major human diseases analysed, Chagas’ disease the existing host population infected, with the frequency of ‘encounters’ is the only one that clearly originated in the New World. For two (opportunities for transmission, including indirect ‘encounters’ via others, syphilis and tuberculosis, the debate is unresolved: it remains vectors) between an individual of the existing host and of the new host, uncertain in which hemisphere syphilis originated, and whether and with the probability of transmission per encounter. p decreases with tuberculosis originated independently in both hemispheres or was increasing phylogenetic distance between the existing host and new host. brought to the Americas by Europeans. Nothing is known about the p also varies among microbes (for example, trypanosomes and geographic origins of rotavirus, rubella, tetanus and typhus. For all of flaviviruses infect a wide taxonomic range of hosts, while plasmodia and simian foamy viruses infect only a narrow range), and this variation is the other 18 major pathogens, Old World origins are certain or related to a microbe’s characteristics, such as its ability to generate probable. genetic variability, or its ability to overcome host molecular barriers of Our preceding discussion of the animal origins of human patho- potential new hosts (such as humoral and cellular defenses or lack of cell gens may help explain this asymmetry. More temperate diseases arose membrane receptors essential for microbe entry into host cells). in the Old World than New World because far more animals that These considerations illuminate different reasons why a given could furnish ancestral pathogens were domesticated in the Old animal host species may or may not become a source of many World. Of the world’s 14 major species of domestic mammalian infections in humans. For instance, despite chimpanzees’ very low livestock, 13, including the five most abundant species with which abundance and infrequent encounters with humans, they have we come into closest contact (cow, sheep, goat, pig and horse), ori- donated to us numerous zoonoses (diseases that still mainly afflict animals) and one or two established human diseases (AIDS and ginated in the Old World . The sole livestock species domesticated in possibly hepatitis B) because of their close phylogenetic relationship to the New World was the llama, but it is not known to have infected us 1,2 humans. Despite their large phylogenetic distance from humans, many with any pathogens —perhaps because its traditional geographic of our zoonoses and probably two of our established diseases (plague range was confined to the Andes, it was not milked or ridden or and typhus) have been acquired from rodents, because of their high hitched to ploughs, and it was not cuddled or kept indoors (as are abundance and frequent encounters with humans in dwellings. some calves, lambs and piglets). Among the reasons why far more Similarly, about half of our established temperate diseases have been tropical diseases (nine versus one) arose in the Old World than the acquired from domestic livestock, because of high local abundance and New World are that the genetic distance between humans and New very frequent contact. Conversely, elephants and bats are not known to World monkeys is almost double that between humans and Old have donated directly to us any established diseases and rarely donate World monkeys, and is many times that between humans and Old zoonoses, because they are heavily penalized on two or three counts: large phylogenetic distance, infrequent encounters with humans, and World apes; and that much more evolutionary time was available for (in the case of elephants) low abundance. One might object that Nipah, transfers from animals to humans in the Old World (about 5 million severe acute respiratory syndrome (SARS) and rabies viruses do infect years) than in the New World (about 14,000 years). humans from bats, but these apparent exceptions actually support our conclusion. While bats may indeed be the primary reservoir for Nipah Outlook and future research directions and SARS, human infections by these viruses are acquired mainly from Many research directions on infectious disease origins merit more intermediate animal hosts that frequently encounter humans effort. We conclude by calling attention to two such directions: cla- (respectively, domestic pigs, and wild animals sold for food). The rare rifying the origins of existing major diseases, and surveillance for cases of rabies transmission directly to humans from bats arise because rabies changes a bat’s behaviour so that it does encounter and early detection of new potentially major diseases. bite humans, which a healthy bat (other than a vampire bat) would Origins of established diseases. This review illustrates big gaps in never do. our understanding of the origins of even the established major infec- Transition from Stage 2 to Stage 3 or 4. Although some Stage 2 and 3 tious diseases. Almost all the studies that we have reviewed were pathogens, such as the anthrax and Marburg agents, are virulent and based on specimens collected opportunistically from domestic ani- feared, they claim few victims at present. Yet if they made the transition mals and a few easily sampled wild animal species, rather than on to Stage 4 or 5, their global impact would be devastating. Why do animal systematic surveys for particular classes of agents over the spectrum pathogens that have survived the initial jump across species lines into a of domestic and wild animals. A case in point is our ignorance even human host (Stages 1 to 2) usually reach a dead end there, and not about smallpox virus, the virus that has had perhaps the greatest evolve past Stages 3 and 4 into major diseases confined to humans (Stage 5)? Barriers between Stages 2 and 3 (consider the rabies virus) impact on human history in the past 4,000 years. Despite some include differences between human and animal behaviour affecting knowledge of poxviruses infecting our domestic mammals, we know transmission (for example, animals often bite humans but humans little about poxvirus diversity among African rodents, from which rarely bite other humans); a pathogen’s need to evolve adaptations to those poxviruses of domestic mammals are thought to have evolved. the new human host and possibly also to a new vector; and obstacles to We do not even know whether ‘camelpox’, the closest known relative a pathogen’s spread between human tissues (for example, BSE is of smallpox virus, is truly confined to camels as its name implies restricted to the central nervous system and lymphoid tissue). Barriers or is instead a rodent virus with a broad host range. There could be between Stages 3 and 4 (consider Ebola virus) include those related to still-unknown poxviruses more similar to smallpox virus in yet human population size and to transmission efficiency between humans. unstudied animal reservoirs, and those unknown poxviruses could The emergence of novel pathogens is now being facilitated by modern be important not only as disease threats but also as reagents for drug developments exposing more potential human victims and/or making 24–27 transmission between humans more efficient than before . These and vaccine development. developments include blood transfusion (hepatitis C), the commercial Equally basic questions arise for other major pathogens. While bushmeat trade (retroviruses), industrial food production (bovine falciparum malaria, an infection imposing one of the heaviest global spongiform encephalitis, BSE), international travel (cholera), burdens today, seems to have originated from a bird parasite whose intravenous drug use (HIV), vaccine production (simian virus 40, descendants include both the Plasmodium falciparum infecting SV40), and susceptible pools of elderly, antibiotic-treated, humans and the P. reichenowii infecting chimpanzees, malaria immunosuppressed patients (see Supplementary Note S2 for details). researchers still debate whether the bird parasite was introduced to © 2007Nature PublishingGroup NATUREjVol 447j17 May 2007 REVIEWS both humans and chimpanzees a few thousand years ago in asso- present in the animals they hunt (for example, retroviruses among ciation with human agriculture, or instead more than five million hunters of non-human primates), as well as generically using broad years ago before the split of humans and chimpanzees from each screening tools such as viral microarrays and random amplification 13 18 other . 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Nature Med. 10, S70–S76 (2004). infections can be monitored over time and traced to other people Supplementary Information is linked to the online version of the paper at in contact with them. One of us (N.D.W.) has been working in www.nature.com/nature. Cameroon to monitor microbes in people who hunt wild game, in other people in their community, and in their animal prey . The Acknowledgements We thank L. Krain for assistance with Supplementary Note S10; M. Antolin, D. Burke, L. Fleisher, E. Holmes, L. Real, A. Rimoin, R. Weiss and study is now expanding to other continents and to monitor domestic M. Woolhouse for comments; and many other colleagues for providing animals (such as dogs) that live in close proximity to humans but information. This work was supported by an NIH Director’s Pioneer Award and are exposed to wild animals through hunting and scavenging. Fogarty International Center IRSDA Award (to N.D.W.), a W. W. Smith Foundation Monitoring of people, animals, and animal die-offs will serve as award (to N.D.W.), and National Geographic Society awards (to J.D. and N.D.W.). an early warning system for disease emergence, while also providing Author Information Reprints and permissions information is available at a unique archive of pathogens infecting humans and the animals to www.nature.com/reprints. The authors declare no competing financial interests. which we are exposed. Specimens from such highly exposed human Correspondence should be addressed to N.W. ([email protected]) or J.D. populations could be screened specifically for agents known to be ([email protected]). © 2007Nature PublishingGroup http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Pubmed Central

Origins of major human infectious diseases

Wolfe, Nathan D.; Dunavan, Claire Panosian; Diamond, Jared
Nature , Volume 447 (7142) – Mar 1, 168
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Vol 447j17 May 2007jdoi:10.1038/nature05775 REVIEWS 1 2 3 Nathan D. Wolfe , Claire Panosian Dunavan & Jared Diamond Many of the major human infectious diseases, including some now confined to humans and absent from animals, are ‘new’ ones that arose only after the origins of agriculture. Where did they come from? Why are they overwhelmingly of Old World origins? Here we show that answers to these questions are different for tropical and temperate diseases; for instance, in the relative importance of domestic animals and wild primates as sources. We identify five intermediate stages through which a pathogen exclusively infecting animals may become transformed into a pathogen exclusively infecting humans. We propose an initiative to resolve disputed origins of major diseases, and a global early warning system to monitor pathogens infecting individuals exposed to wild animals. uman hunter/gatherer populations currently suffer, and unicellular microbial pathogens. We exclude macroparasites (in presumably have suffered for millions of years, from infec- the sense of ref. 7), as well as normally benign commensals that cause tious diseases similar or identical to diseases of other wild serious illness only in weakened hosts. The extensive Supplementary H primate populations. However, the most important infec- Information provides details and references on our 25 diseases, tious diseases of modern food-producing human populations also robustness tests of our conclusions, factors affecting transitions include diseases that could have emerged only within the past 11,000 between disease stages, and modern practices altering the risk of 1,2 years, following the rise of agriculture . We infer this because, as emergence of new diseases. discussed below, these diseases can only be sustained in large dense Evolutionary stages human populations that did not exist anywhere in the world before agriculture. What were the sources of our major infectious diseases, Box 1 delineates five intergrading stages (Fig. 1) through which a including these ‘new’ ones? Why do so many animal pathogens, pathogen exclusively infecting animals (Stage 1) may become trans- including virulent viruses like Ebola and Marburg, periodically formed into a pathogen exclusively infecting humans (Stage 5). infect human hosts but then fail to establish themselves in human Supplementary Table S1 assigns each of the 25 major diseases dis- populations? cussed (Supplementary Note S1) to one of these five stages. A tentative earlier formulation noted that major infectious dis- A large literature discusses the conditions required for a Stage 5 2,7 eases of temperate zones seem to have arisen overwhelmingly in the epidemic to persist . Briefly, if the disease infects only humans and Old World (Africa, Asia and Europe), often from diseases of Old lacks an animal or environmental reservoir, each infected human World domestic animals. Hence one goal of this article is to re- introduced into a large population of susceptible individuals must appraise that conclusion in the light of studies of the past decade. on average give rise during his/her contagious lifespan to an infection Another goal is to extend the analysis to origins of tropical diseases . in at least one other individual. Persistence depends on factors such We shall show that they also arose mainly in the Old World, but for as the duration of a host’s infectivity; the rate of infection of new different reasons, and mostly not from diseases of domestic animals. hosts; rate of development of host protective immunity; and host These results provide a framework for addressing unanswered population density, size and structure permitting the pathogen’s questions about the evolution of human infectious diseases—ques- regional persistence despite temporary local extinctions. tions not only of practical importance to physicians, and to all the rest Less well understood are two of the critical transitions between of us as potential victims, but also of intellectual interest to historians stages, discussed in Box 2. One is the transition from Stage 1 to Stage and evolutionary biologists. Historians increasingly recognize that 2, when a pathogen initially confined to animals first infects humans. infectious diseases have had major effects on the course of history; The other is the transition from Stage 2 to Stages 3 and 4 (see also for example, on the European conquest of Native Americans and Supplementary Note S2), when a pathogen of animal origin that is Pacific Islanders, the inability of Europeans to conquer the Old nevertheless transmissible to humans evolves the ability to sustain World tropics for many centuries, the failure of Napoleon’s invasion many cycles of human-to-human transmission, rather than just a few of Russia, and the failure of the French attempt to complete con- cycles before the outbreak dies out (as seen in modern Ebola out- 4–6 struction of a Panama Canal . Evolutionary biologists realize that breaks). infectious diseases, as a leading cause of human morbidity and mor- 2,7 tality, have exerted important selective forces on our genomes . Database and conclusions We begin by defining five stages in the evolutionary transforma- Database. Supplementary Table S1 lists 10 characteristics for each tion of an animal pathogen into a specialized pathogen of humans, of 25 important ‘temperate’ (15) and ‘tropical’ (10) diseases (see and by considering why so many pathogens fail to make the trans- Supplementary Note S3 for details of this distinction). Our aim ition from one stage to the next. We then assemble a database of 15 was to select well-defined diseases causing the highest mortality temperate and 10 tropical diseases of high evolutionary and/or his- and/or morbidity and hence of the highest historical and evolution- torical impact, and we compare their characteristics and origins. Our ary significance (see Supplementary Note S1 for details of our selec- concluding section lays out some unresolved questions and suggests tion criteria). Of the 25 diseases, we selected 17 because they are the two expanded research priorities. We restrict our discussion to ones assessed by ref. 8 as imposing the heaviest world burdens today 1 2 Department of Epidemiology, School of Public Health, University of California, Los Angeles 90095-1772, USA. Division of Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles 90095-1688, USA. Departments of Geography and of Environmental Health Sciences, University of California, Los Angeles 90095-1524, USA. © 2007Nature PublishingGroup REVIEWS NATUREjVol 447j17 May 2007 Are our conclusions robust to variations in these selection criteria? Box 1 j Five stages leading to endemic human diseases For about a dozen diseases with the highest modern or historical We delineate five stages in the transformation of an animal pathogen burdens (for example, AIDS, malaria, plague, smallpox), there can into a specialized pathogen of humans (Fig. 1). There is no inevitable be little doubt that they must be included, but one could debate some progression of microbes from Stage 1 to Stage 5: at each stage many of the next choices. Hence we drew up three alternative sets of dis- microbes remain stuck, and the agents of nearly half of the 25 eases sharing a first list of 16 indisputable major diseases but differing important diseases we selected for analysis (Supplementary Table S1) in the next choices, and we performed all 10 analyses described below have not reached Stage 5. Stage 1. A microbe that is present in animals but that has not on all three sets. It turned out that, with one minor exception, the been detected in humans under natural conditions (that is, three sets yielded qualitatively the same conclusions for all 10 analyses, excluding modern technologies that can inadvertently transfer although differing in their levels of statistical significance (see Sup- microbes, such as blood transfusion, organ transplants, or plementary Note S4). Thus, our conclusions do seem to be robust. hypodermic needles). Examples: most malarial plasmodia, which Temperate/tropical differences. Comparisons of these temperate tend to be specific to one host species or to a closely related and tropical diseases yield the following conclusions: group of host species. A higher proportion of the diseases is transmitted by insect . Stage 2. A pathogen of animals that, under natural conditions, vectors in the tropics (8/10) than in the temperate zones (2/ has been transmitted from animals to humans (‘primary infection’) but has not been transmitted between humans 15) (P, 0.005, x -test, degrees of freedom, d.f.5 1). This dif- (‘secondary infection’). Examples: anthrax and tularemia bacilli, ference may be partly related to the seasonal cessations or and Nipah, rabies and West Nile viruses. declines of temperate insect activity. Stage 3. Animal pathogens that can undergo only a few cycles of A higher proportion (P5 0.009) of the diseases conveys long- secondary transmission between humans, so that occasional lasting immunity (11/15) in the temperate zones than in the human outbreaks triggered by a primary infection soon die out. tropics (2/10). Examples: Ebola, Marburg and monkeypox viruses. . Animal reservoirs are more frequent (P, 0.005) in the tropics . Stage 4. A disease that exists in animals, and that has a natural (8/10) than in the temperate zones (3/15). The difference is in (sylvatic) cycle of infecting humans by primary transmission the reverse direction (P5 0.1, NS, not significant) for envir- from the animal host, but that also undergoes long sequences of secondary transmission between humans without the onmental reservoirs (1/10 versus 6/15), but those envir- involvement of animal hosts. We arbitrarily divide Stage 4 into onmental reservoirs that do exist are generally not of major three substages distinguished by the relative importance of significance except for soil bearing tetanus spores. primary and secondary transmission: Most of the temperate diseases (12/15) are acute rather than Stage 4a. Sylvatic cycle much more important than direct slow, chronic, or latent: the patient either dies or recovers human-to-human spread. Examples: Chagas’ disease and (more within one to several weeks. Fewer (P5 0.01) of the tropical frequent secondary transmission approaching Stage 4b) yellow diseases are acute: 3/10 last for one or two weeks, 3/10 last for fever. weeks to months or years, and 4/10 last for many months to Stage 4b. Both sylvatic and direct transmission are important. decades. Example: dengue fever in forested areas of West Africa and Southeast Asia. A somewhat higher proportion of the diseases (P5 0.08, NS) Stage 4c. The greatest spread is between humans. Examples: belongs to Stage 5 (strictly confined to humans) in the tem- influenza A, cholera, typhus and West African sleeping sickness. perate zones (10/15 or 11/15) than in the tropics (3/10). The Stage 5. A pathogen exclusive to humans. Examples: the agents paucity of Stage 2 and Stage 3 diseases (a total of only 5 such causing falciparum malaria, measles, mumps, rubella, smallpox diseases) on our list of 25 major human diseases is noteworthy, and syphilis. In principle, these pathogens could have become because some Stage 2 and Stage 3 pathogens (such as anthrax confined to humans in either of two ways: an ancestral pathogen and Ebola) are notoriously virulent, and because theoretical already present in the common ancestor of chimpanzees and reasons are often advanced (but also denied) as to why Stage 5 humans could have co-speciated long ago, when the chimpanzee microbes with long histories of adaptation to humans should and human lineages diverged around five million years ago; or else an animal pathogen could have colonized humans more tend to evolve low morbidity and mortality and not cause recently and evolved into a specialized human pathogen. Co- major diseases. We discuss explanations for this outcome in speciation accounts well for the distribution of simian foamy Supplementary Note S5. viruses of non-human primates, which are lacking and Most (10/15) of the temperate diseases, but none of the tropical presumably lost in humans: each virus is restricted to one diseases (P, 0.005), are so-called ‘crowd epidemic diseases’ (aster- primate species, but related viruses occur in related primate isked in Supplementary Table S1), defined as ones occurring locally species . While both interpretations are still debated for as a brief epidemic and capable of persisting regionally only in large falciparum malaria, the latter interpretation of recent origins is human populations. This difference is an immediate consequence of widely preferred for most other human Stage 5 diseases of the differences enumerated in the preceding five paragraphs. If a Supplementary Table S1. disease is acute, efficiently transmitted, and quickly leaves its victim either dead or else recovering and immune to re-infection, the epi- (they have the highest disability-adjusted life years (DALY) scores). demic soon exhausts the local pool of susceptible potential victims. If Of the 17 diseases, 8 are temperate (hepatitis B, influenza A, measles, in addition the disease is confined to humans and lacks significant pertussis, rotavirus A, syphilis, tetanus and tuberculosis), and 9 are animal and environmental reservoirs, depletion of the local pool of tropical (acquired immune deficiency syndrome (AIDS), Chagas’ potential victims in a small, sparse human population results in local disease, cholera, dengue haemorrhagic fever, East and West African termination of the epidemic. If, however, the human population is sleeping sicknesses, falciparum and vivax malarias, and visceral leish- large and dense, the disease can persist by spreading to infect people maniasis). We selected eight others (temperate diphtheria, mumps, in adjacent areas, and then returning to the original area in a later plague, rubella, smallpox, typhoid and typhus, plus tropical yellow year, when births and growth have regenerated a new crop of prev- fever) because they imposed heavy burdens in the past, although iously unexposed non-immune potential victims. Empirical epide- modern medicine and public health have either eradicated them miological studies of disease persistence or disappearance in isolated (smallpox) or reduced their burden. Except for AIDS, dengue fever, human populations of various sizes have yielded estimates of the and cholera, which have spread and attained global impact in modern population required to sustain a crowd disease: at least several hun- 2,7 times, most of these 25 diseases have been important for more than dred thousand people in the cases of measles, rubella and pertussis . two centuries. But human populations of that size did not exist anywhere in the © 2007Nature PublishingGroup NATUREjVol 447j17 May 2007 REVIEWS Transmission Stage to humans Stage 5: exclusive Only from human agent humans Stage 4: From animals long outbreak or (many cycles) humans Stage 3: From animals limited or (few cycles) outbreak humans Stage 2: primary Only from animals infection Stage 1: agent only None in animals Rabies Ebola Dengue HIV-1 M Figure 1 | Illustration of the five stages through which pathogens of process, ranging from rabies (still acquired only from animals) to HIV-1 animals evolve to cause diseases confined to humans. (See Box 1 for (now acquired only from humans). details.) The four agents depicted have reached different stages in the world until the steep rise in human numbers that began around Supplementary Note S7). Why do temperate and tropical human 1,9 11,000 years ago with the development of agriculture . Hence the diseases differ so markedly in their animal origins? Many (4/10) crowd epidemic diseases of the temperate zones must have evolved tropical diseases (AIDS, dengue fever, vivax malaria, yellow fever) since then. but only 1/15 temperate diseases (hepatitis B) have wild non-human Of course, this does not mean that human hunter/gatherer com- primate origins (P5 0.04). This is because although non-human munities lacked infectious diseases. Instead, like the sparse popula- primates are the animals most closely related to humans and hence tions of our primate relatives, they suffered from infectious diseases pose the weakest species barriers to pathogen transfer, the vast major- with characteristics permitting them to persist in small populations, ity of primate species is tropical rather than temperate. Conversely, unlike crowd epidemic diseases. Those characteristics include: occur- few tropical but many temperate diseases arose from domestic ani- rence in animal reservoirs as well as in humans (such as yellow fever); mals, and this is because domestic animals live mainly in the tem- perate zones, and their concentration there was formerly even more incomplete and/or non-lasting immunity, enabling recovered patients to remain in the pool of potential victims (such as malaria); lop-sided (see Supplementary Note S8). and a slow or chronic course, enabling individual patients to con- A final noteworthy point about animal-derived human pathogens tinue to infect new victims over years, rather than for just a week or is that virtually all arose from pathogens of other warm-blooded two (such as Chagas’ disease). vertebrates, primarily mammals plus in two cases (influenza A and Pathogen origins. (See details for each disease in Supplementary ultimately falciparum malaria) birds. This comes as no surprise, con- sidering the species barrier to pathogen transfer posed by phylogen- Note S10). Current information suggests that 8 of the 15 temperate diseases probably or possibly reached humans from domestic ani- etic distance (Box 2). An expression of this barrier is that primates mals (diphtheria, influenza A, measles, mumps, pertussis, rotavirus, constitute only 0.5% of all vertebrate species but have contributed smallpox, tuberculosis); three more probably reached us from apes about 20% of our major human diseases. Expressed in another way, (hepatitis B) or rodents (plague, typhus); and the other four (rubella, the number of major human diseases contributed, divided by the syphilis, tetanus, typhoid) came from still-unknown sources (see number of animal species in the taxonomic group contributing those Supplementary Note S6). Thus, the rise of agriculture starting diseases, is approximately 0.2 for apes, 0.017 for non-human pri- 11,000 years ago played multiple roles in the evolution of animal mates other than apes, 0.003 for mammals other than primates, 1,4,10 pathogens into human pathogens . Those roles included both 0.00006 for vertebrates other than mammals, and either 0 or else generation of the large human populations necessary for the evolu- 0.000003 (if cholera really came from aquatic invertebrates) for ani- tion and persistence of human crowd diseases, and generation of mals other than vertebrates (see Supplementary Note S9). large populations of domestic animals, with which farmers came into Geographic origins. To an overwhelming degree, the 25 major much closer and more frequent contact than hunter/gatherers had human pathogens analysed here originated in the Old World. That with wild animals. Moreover, as illustrated by influenza A, these proved to be of great historical importance, because it facilitated domestic animal herds served as efficient conduits for pathogen the European conquest of the New World (the Americas). Far more transfers from wild animals to humans, and in the process may have Native Americans resisting European colonists died of newly intro- evolved specialized crowd diseases of their own. duced Old World diseases than of sword and bullet wounds. Those It is interesting that fewer tropical than temperate pathogens ori- invisible agents of New World conquest were Old World microbes to ginated from domestic animals: not more than three of the ten trop- which Europeans had both some acquired immunity based on indi- ical diseases of Supplementary Table S1, and possibly none (see vidual exposure and some genetic resistance based on population © 2007Nature PublishingGroup REVIEWS NATUREjVol 447j17 May 2007 exposure over time, but to which previously unexposed Native 1,4–6 American populations had no immunity or resistance . In con- Box 2 Transitions between stages trast, no comparably devastating diseases awaited Europeans in the Transition from Stage 1 to Stage 2. Most animal pathogens are not New World, which proved to be a relatively healthy environment for transmitted tohumans, that is, they do not even pass from Stage 1 toStage Europeans until yellow fever and malaria of Old World origins 2. This problem of cross-species infection has been discussed 20–23 arrived . previously . Briefly, the probability-per-unit-time (p) of infection of an individual of a new (that is, new recipient) host species increases with the Why was pathogen exchange between Old and New Worlds so abundance of theexisting (that is, existingdonor) host, with thefraction of unequal? Of the 25 major human diseases analysed, Chagas’ disease the existing host population infected, with the frequency of ‘encounters’ is the only one that clearly originated in the New World. For two (opportunities for transmission, including indirect ‘encounters’ via others, syphilis and tuberculosis, the debate is unresolved: it remains vectors) between an individual of the existing host and of the new host, uncertain in which hemisphere syphilis originated, and whether and with the probability of transmission per encounter. p decreases with tuberculosis originated independently in both hemispheres or was increasing phylogenetic distance between the existing host and new host. brought to the Americas by Europeans. Nothing is known about the p also varies among microbes (for example, trypanosomes and geographic origins of rotavirus, rubella, tetanus and typhus. For all of flaviviruses infect a wide taxonomic range of hosts, while plasmodia and simian foamy viruses infect only a narrow range), and this variation is the other 18 major pathogens, Old World origins are certain or related to a microbe’s characteristics, such as its ability to generate probable. genetic variability, or its ability to overcome host molecular barriers of Our preceding discussion of the animal origins of human patho- potential new hosts (such as humoral and cellular defenses or lack of cell gens may help explain this asymmetry. More temperate diseases arose membrane receptors essential for microbe entry into host cells). in the Old World than New World because far more animals that These considerations illuminate different reasons why a given could furnish ancestral pathogens were domesticated in the Old animal host species may or may not become a source of many World. Of the world’s 14 major species of domestic mammalian infections in humans. For instance, despite chimpanzees’ very low livestock, 13, including the five most abundant species with which abundance and infrequent encounters with humans, they have we come into closest contact (cow, sheep, goat, pig and horse), ori- donated to us numerous zoonoses (diseases that still mainly afflict animals) and one or two established human diseases (AIDS and ginated in the Old World . The sole livestock species domesticated in possibly hepatitis B) because of their close phylogenetic relationship to the New World was the llama, but it is not known to have infected us 1,2 humans. Despite their large phylogenetic distance from humans, many with any pathogens —perhaps because its traditional geographic of our zoonoses and probably two of our established diseases (plague range was confined to the Andes, it was not milked or ridden or and typhus) have been acquired from rodents, because of their high hitched to ploughs, and it was not cuddled or kept indoors (as are abundance and frequent encounters with humans in dwellings. some calves, lambs and piglets). Among the reasons why far more Similarly, about half of our established temperate diseases have been tropical diseases (nine versus one) arose in the Old World than the acquired from domestic livestock, because of high local abundance and New World are that the genetic distance between humans and New very frequent contact. Conversely, elephants and bats are not known to World monkeys is almost double that between humans and Old have donated directly to us any established diseases and rarely donate World monkeys, and is many times that between humans and Old zoonoses, because they are heavily penalized on two or three counts: large phylogenetic distance, infrequent encounters with humans, and World apes; and that much more evolutionary time was available for (in the case of elephants) low abundance. One might object that Nipah, transfers from animals to humans in the Old World (about 5 million severe acute respiratory syndrome (SARS) and rabies viruses do infect years) than in the New World (about 14,000 years). humans from bats, but these apparent exceptions actually support our conclusion. While bats may indeed be the primary reservoir for Nipah Outlook and future research directions and SARS, human infections by these viruses are acquired mainly from Many research directions on infectious disease origins merit more intermediate animal hosts that frequently encounter humans effort. We conclude by calling attention to two such directions: cla- (respectively, domestic pigs, and wild animals sold for food). The rare rifying the origins of existing major diseases, and surveillance for cases of rabies transmission directly to humans from bats arise because rabies changes a bat’s behaviour so that it does encounter and early detection of new potentially major diseases. bite humans, which a healthy bat (other than a vampire bat) would Origins of established diseases. This review illustrates big gaps in never do. our understanding of the origins of even the established major infec- Transition from Stage 2 to Stage 3 or 4. Although some Stage 2 and 3 tious diseases. Almost all the studies that we have reviewed were pathogens, such as the anthrax and Marburg agents, are virulent and based on specimens collected opportunistically from domestic ani- feared, they claim few victims at present. Yet if they made the transition mals and a few easily sampled wild animal species, rather than on to Stage 4 or 5, their global impact would be devastating. Why do animal systematic surveys for particular classes of agents over the spectrum pathogens that have survived the initial jump across species lines into a of domestic and wild animals. A case in point is our ignorance even human host (Stages 1 to 2) usually reach a dead end there, and not about smallpox virus, the virus that has had perhaps the greatest evolve past Stages 3 and 4 into major diseases confined to humans (Stage 5)? Barriers between Stages 2 and 3 (consider the rabies virus) impact on human history in the past 4,000 years. Despite some include differences between human and animal behaviour affecting knowledge of poxviruses infecting our domestic mammals, we know transmission (for example, animals often bite humans but humans little about poxvirus diversity among African rodents, from which rarely bite other humans); a pathogen’s need to evolve adaptations to those poxviruses of domestic mammals are thought to have evolved. the new human host and possibly also to a new vector; and obstacles to We do not even know whether ‘camelpox’, the closest known relative a pathogen’s spread between human tissues (for example, BSE is of smallpox virus, is truly confined to camels as its name implies restricted to the central nervous system and lymphoid tissue). Barriers or is instead a rodent virus with a broad host range. There could be between Stages 3 and 4 (consider Ebola virus) include those related to still-unknown poxviruses more similar to smallpox virus in yet human population size and to transmission efficiency between humans. unstudied animal reservoirs, and those unknown poxviruses could The emergence of novel pathogens is now being facilitated by modern be important not only as disease threats but also as reagents for drug developments exposing more potential human victims and/or making 24–27 transmission between humans more efficient than before . These and vaccine development. developments include blood transfusion (hepatitis C), the commercial Equally basic questions arise for other major pathogens. While bushmeat trade (retroviruses), industrial food production (bovine falciparum malaria, an infection imposing one of the heaviest global spongiform encephalitis, BSE), international travel (cholera), burdens today, seems to have originated from a bird parasite whose intravenous drug use (HIV), vaccine production (simian virus 40, descendants include both the Plasmodium falciparum infecting SV40), and susceptible pools of elderly, antibiotic-treated, humans and the P. reichenowii infecting chimpanzees, malaria immunosuppressed patients (see Supplementary Note S2 for details). researchers still debate whether the bird parasite was introduced to © 2007Nature PublishingGroup NATUREjVol 447j17 May 2007 REVIEWS both humans and chimpanzees a few thousand years ago in asso- present in the animals they hunt (for example, retroviruses among ciation with human agriculture, or instead more than five million hunters of non-human primates), as well as generically using broad years ago before the split of humans and chimpanzees from each screening tools such as viral microarrays and random amplification 13 18 other . 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Infectious diseases and human population history. tification of porcine rubulavirus and the Mapuera virus in bats as the Bioscience 46, 115–126 (1996). closest known relatives of mumps virus mean that pigs infected 3. Diamond, J. & Panosian, C. in When Disease Makes History: Epidemics and Great Historical Turning Points (ed. Ha¨ma¨la¨inen, P.) 17–44 (Helsinki Univ. Press, 2006). humans, or that human mumps infected pigs, or that bats indepen- 4. McNeill, W. H. Plagues and Peoples (Anchor, Garden City, 1976). dently infected both humans and pigs? Is human tuberculosis des- 5. Crosby, A. W. Ecological Imperialism: the Biological Expansion of Europe 900–1900 cended from a ruminant mycobacterium that recently infected (Cambridge Univ. Press, Cambridge, UK, 1986). humans from domestic animals (a formerly prevalent view), or from 6. Ramenofsky, A. 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Nature Med. 10, S70–S76 (2004). infections can be monitored over time and traced to other people Supplementary Information is linked to the online version of the paper at in contact with them. One of us (N.D.W.) has been working in www.nature.com/nature. Cameroon to monitor microbes in people who hunt wild game, in other people in their community, and in their animal prey . The Acknowledgements We thank L. Krain for assistance with Supplementary Note S10; M. Antolin, D. Burke, L. Fleisher, E. Holmes, L. Real, A. Rimoin, R. Weiss and study is now expanding to other continents and to monitor domestic M. Woolhouse for comments; and many other colleagues for providing animals (such as dogs) that live in close proximity to humans but information. This work was supported by an NIH Director’s Pioneer Award and are exposed to wild animals through hunting and scavenging. Fogarty International Center IRSDA Award (to N.D.W.), a W. W. Smith Foundation Monitoring of people, animals, and animal die-offs will serve as award (to N.D.W.), and National Geographic Society awards (to J.D. and N.D.W.). an early warning system for disease emergence, while also providing Author Information Reprints and permissions information is available at a unique archive of pathogens infecting humans and the animals to www.nature.com/reprints. The authors declare no competing financial interests. which we are exposed. Specimens from such highly exposed human Correspondence should be addressed to N.W. ([email protected]) or J.D. populations could be screened specifically for agents known to be ([email protected]). © 2007Nature PublishingGroup

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Nature – Pubmed Central

Published: Mar 1, 168

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