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Of mice and men: defining, categorizing and understanding the significance of zoonotic infections

2010; Elsevier BV; Volume: 17; Issue: 3 Linguagem: Inglês

10.1111/j.1469-0691.2010.03444.x

1469-0691

Γεώργιος Παππάς,

Animal Disease Management and Epidemiology

The increasingly anthropocentric model by which humans have grown to theoretically view the surrounding world is often tested in practice, be it climate changes and global warming, the complex consequences of natural disasters, or the outcomes of interaction with the rest of living creatures. In medicine, this anthropocentric model of thinking is nowhere more obvious than in the case of zoonotic infections, the burden and significance of which are constantly under-appraised. Zoonotic infections remain an ever-growing unsolved puzzle, serving typically as an umbrella term under which numerous infectious diseases are shelved, in order to ignore not only their medical and veterinarian-related burden, but also, and more importantly, their major socio-economic correlations, which pertain to global and regional political ethics, and thus should preferably remain unnoticed. What is a zoonotic infection and is there any reason for having such a classification? What do we conclude about an infectious agent by terming it as zoonotic? Zoonosis is a complex Greek word deriving from the words 'ζωoν' (zoon), which means animal, and 'νóσoζ' (nosos), which means disease. In broad terms, a zoonotic infection is one that can be transmitted by animals to humans. A definite clarification of the term though does not exist, and one may wonder whether we need one, apart from the broad characterization offered above. But a definition is needed, because it will allow for proper grouping of appropriate pathogens and direct understanding of their correlations and broader, non-medical parameters. A proper definition would further allow for functional targeting of the factors that allow for the continuing prevalence of zoonotic infections through public health strategies and adaptations of social, medical and veterinarian policies that affect the impact of zoonoses. The initial World Health Organization (WHO) definition of zoonotic infections in 1951 referred to any disease naturally transmitted between vertebrate animals and humans, either way, but excluded, crucially, experimental transmissions and toxin-mediated transmissions, and further excluded indirect participation of animals or vectors in the disease transmission chain. The term 'anthroponoses' (from the Greek word 'ανϑρωπoζ', which stands for human) had been coined to characterize diseases whose source was an infectious human, and the term 'sapronoses' (from the ancient Greek word 'σαπρóζ', which means putrescent or degradable) referred to diseases whose origin was an abiotic substrate [1Hubalek Z Emerging human infectious diseases: anthroponoses, zoonoses, and sapronoses.Emerg Infect Dis. 2003; 9: 403-404Crossref PubMed Scopus (116) Google Scholar]. Zoonoses were further characterized as anthropozoonoses, when transmitted from animals to humans, and zooanthroponoses when transmitted vice versa. The term 'amphixenoses' (the Greek words 'αμϕî', which means bi-, and 'ζ∈νoç', which means host) was also limitedly used to describe zoonotic infections that are transmissible either way. All these sub-terms were subsequently abandoned by WHO expert committees. Our anthropocentric view of nature means that in general the term 'zoonoses' refers to disease transmissible to humans, while the inverse remain a subject localized to the interest of environmental specialists. This widely accepted definition not only underlines the extent of the zoonotic impact on human health, but also underscores the categorization issues that emerge: for example, influenza A (H5N1) virus, the most alarming avian influenza strain, is a typical zoonotic infection because it demands close human contact with animal hosts for the infection to spread to man. On the other hand, the novel swine influenza A (H1N1) virus is also typically a zoonotic infection, transmitted from swine hosts to humans; however, the ensuing direct human to human transmission was the signifying characteristic of the pathogen and the major factor leading to the 2009 pandemic. Despite being strictly a zoonotic infection, sharing initially certain socio-political characteristics with other typical zoonotic viral infections regarding its birth and initial contact with humans, its spread dynamics and human morbidity potential are irrelevant to its zoonotic nature. The same could be said about HIV, the simian origin of which would allow for a zoonotic characterization, and SARS-CoV, which originated in horseshoe bats [2Li W Shi Z Yu M et al.Bats are natural reservoirs of SARS‐like coronaviruses.Science. 2005; 310: 676-679Crossref PubMed Scopus (1874) Google Scholar]. Categorization is further blurred when considering agents usually transmitted from human to human through an arthropod vector (for example dengue), agents though that require for their lifecycle an invertebrate animal host: these are not strictly zoonoses, because the animal host is invertebrate, but they do share certain socio-ecological characteristics with the typical zoonotic infections. Moreover, a number of pathogens require a vertebrate host but can replicate in and infect humans through contact with abiotic material: often referred to as 'saprozoonoses' [1Hubalek Z Emerging human infectious diseases: anthroponoses, zoonoses, and sapronoses.Emerg Infect Dis. 2003; 9: 403-404Crossref PubMed Scopus (116) Google Scholar], these agents are not unanimously considered to be of a zoonotic nature. One may wonder why a categorization is needed in the first place. Furthermore, one may wonder why we discuss zoonoses; there are numerous reasons, ranging from those that are historical and philosophical/teleological to pure pragmatism. Zoonoses preceded humanity, adding fuel to a non-anthropocentric view of their existence, their interaction with the human race, and their re-emergence. Hippocrates, among others, has written extensively about this interaction [3Pappas G Kiriaze IJ Falagas ME Insights into infectious disease in the era of Hippocrates.Int J Infect Dis. 2008; 12: 347-350Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar], and the common effect of infectious agents in livestock and humans can be traced as far back as the Ten Plagues of Egypt. 'It will become fine dust over the whole land of Egypt, and festering boils will break out on men and animals throughout the land' [4The Old Testament, Exodus 9:9.Available at: http://www.biblegateway.com/passage/?search=Exodus%209&version=NIV1984Google Scholar], says Exodus 9, describing an airborne infection causing disease in livestock and humans. The Old Testament also carries the description, in the First Book of Samuel, of a lethal outbreak of 'groin tumors' in Philistines, in conjunction with the presence of rats, a possible early description of bubonic plague or tularemia and its association with rodents [5Freeman FR Bubonic plague in the Book of Samuel.J R Soc Med. 2005; 98: 436Crossref PubMed Scopus (17) Google Scholar]. Awareness of this interaction was not lost through the ages: in 1796, Edward Jenner commented that man 'has familiarized himself with a great number of animals which may not, originally, have been intended for his associates', and thus this deviation 'seems to have proven to him a prolific source of diseases' [6Armstrong D Zoonoses.Int J Infect Dis. 2001; 5: 117-118Abstract Full Text PDF PubMed Scopus (1) Google Scholar]. In a courageous attempt to classify existing human pathogens, Taylor et al. [7Taylor LH Latham SM Woolhouse ME Risk factors for human disease emergence.Philos Trans R Soc Lond B Biol Sci. 2001; 356: 983-989Crossref PubMed Scopus (1851) Google Scholar] demonstrated that the majority of these pathogens are zoonotic, comprising 61% of the total of 1415 species. Furthermore, they managed to demonstrate that the vast majority of emerging diseases are caused by a zoonotic pathogen, the percentage reaching 75%. Although the categorization as zoonotic for some of the pathogens by Taylor and colleagues may be doubtful (many being theoretically only zoonotic), and although some of the species implicated are of historical or isolated significance for human health, there still exists an enormous burden of zoonotic agents causing major human morbidity. As discussed in the reviews by Christou and Akritidis in the present issue of Clinical Microbiology and Infection ('The global burden of bacterial and viral zoonotic infections' and 'Parasitic, fungal and prion zoonoses: an expanding universe of candidates for human disease', respectively), the global impact of zoonotic infections is far more significant than indicated by public health and eradication campaigns and scientific research. This underestimated burden is even more troublesome because it transcends the strict medical field, extending to the veterinarian and public health field, and reaching, as will be discussed later, issues of society, state, economy and regional and national and global politics of all sorts. To put it simply, millions of new cases of zoonotic infections are registered annually worldwide, often in clusters irrespective of the disease, with a major morbidity toll that may lapse to chronicity, and considerable mortality. One can anticipate the future to hold an enhanced morbidity burden of zoonotic infections: not only are we able to recognize them better through advanced diagnostics, but medical progress has also created a vast reservoir of potential candidates for infection; in particular, immunocompromized patients build up such a patient pool, developing a wide spectrum of opportunistic infections, many of which were previously considered harmless zoonotic agents, typical examples being human cryptosporidiosis, unknown 40 years ago, and toxoplasmosis or listeriosis in AIDS patients. The world now has become a huge village; extensive population movements take place annually, be it for tourism, leisure or work, or even through military operations. Outbreaks of zoonotic infections in travellers abroad have been increasingly reported, ranging from leptospirosis in adventurous athletes [8Sejvar J Bancroft E Winthrop K et al.Leptospirosis in "Eco‐Challenge" athletes, Malaysian Borneo, 2000.Emerg Infect Dis. 2003; 9: 702-707Crossref PubMed Scopus (240) Google Scholar], to leishmaniasis and Q fever in troops deployed in Iraq and Afghanistan [9Faix DJ Harrison DJ Riddle MS et al.Outbreak of Q fever among US military in western Iraq, June–July 2005.Clin Infect Dis. 2008; 46: e65-e68Crossref PubMed Scopus (57) Google Scholar, 10Myles O Wortmann GW Cummings JF et al.Visceral leishmaniasis: clinical observations in 4 US army soldiers deployed to Afghanistan or Iraq, 2002–2004.Arch Intern Med. 2007; 167: 1899-1901Crossref PubMed Scopus (31) Google Scholar]. Voluntary or war-related immigration further serves as a vehicle for zoonotic infection migration: this has been demonstrated repeatedly regarding brucellosis kinetics [11Pappas G Papadimitriou P Akritidis N Christou L Tsianos EV The new global map of human brucellosis.Lancet Infect Dis. 2006; 6: 91-99Abstract Full Text Full Text PDF PubMed Scopus (1641) Google Scholar]. Zoonotic infection control is a complex issue. Control of human disease, either by eradication or through elimination, may prove futile due to the lack of (and the projected non-development of) efficient vaccines for most of the significant zoonotic pathogens. One can presume that control should be an issue of veterinarians, identifying and eliminating disease in animal hosts. This is not the case though, because numerous zoonotic agents are recognized in wildlife, which is out of veterinary jurisdiction. Even for pathogens that emerge from domestic animals though, control is often unattainable due to inadequate planning or inadequate implementation of relevant campaigns: taking into account that this is often the case in the industrialized world (again the example of brucellosis control in the European Union [12Godfroid J Käsbohrer A Brucellosis in the European Union and Norway at the turn of the twenty‐first century.Vet Microbiol. 2002; 90: 135-145Crossref PubMed Scopus (143) Google Scholar] can serve as an instructive case study), one can imagine how futile such a target is in developing countries with absent or poorly developed medical, veterinary and public health infrastructure. The latter countries are the ones which serve as vast zoonotic reservoirs though: zoonoses have been recognized as diseases of the poor, and this has obvious implications for the way they are confronted by science, health-related project funding bodies and politics. Again using brucellosis as an obvious example for the author (an experience though that could be generalized for numerous other zoonotic agents and various countries, industrialized or not, the US-Mexico border [13Doyle TJ Bryan RT Infectious disease morbidity in the US region bordering Mexico, 1990–1998.J Infect Dis. 2000; 182: 1503-1510Crossref PubMed Scopus (75) Google Scholar, 14Homedes N Ugalde A Globalization and health at the United States‐Mexico border.Am J Public Health. 2003; 93: 2016-2022Crossref PubMed Scopus (55) Google Scholar] being a prime example), a minor outbreak (<10 cases) of foodborne brucellosis in a suburb of the capital, Athens, a few years ago, resulted in extensive media coverage; on the other hand, a rather extensive (more than 80 cases) subsequent outbreak in a rural island of northern Greece [15Vorou R Gkolfinopoulou K Dougas G et al.Local brucellosis outbreak on Thassos, Greece: a preliminary report.Euro Surveill. 2008; 13 (pii: 18910.)PubMed Google Scholar] went unnoticed by the media, despite exhibiting significant evidence of all sorts of policy misdemeanours (illegal animal importation, inadequate implication of preventive policies and subsequent testing, inadequate notification of preceding cases that should serve as an alarm, and so on). The fact that zoonotic control is a political issue though is a rather easy conclusion: the instructive story of a bovine spongiform encephalopathy (BSE) outbreak and its enormous consequences for the economy not only of the affected country but also of numerous others, underlines how a peculiar and vaguely understood zoonotic agent can affect global politics. However, terming zoonoses control as a political issue is also a too broad term to start with: As discussed in the review by Cascio and colleagues in the present issue of Clinical Microbiology and Infection (The socio-ecology of zoonotic infections), approaching the evolution of zoonotic infections should ideally be an interdisciplinary task that should comprise an intelligent political approach with all sorts of medical, veterinarian, public health, animal biology/entomology/ornithology-related, environmental, ecological, evolutionist and socioeconomic parameters. Even if all these parameters are harmonized, one needs to be assured that the public will be receptive: a direct relationship of zoonotic disease prevalence with the health literacy of the public has been demonstrated for certain zoonoses, including brucellosis and rabies [16Pappas G Siozopoulou V Saplaoura K et al.Health literacy in the field of infectious diseases: the paradigm of brucellosis.J Infect. 2007; 54: 40-45Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 17Briggs D Hanlon A World Rabies Day: focusing attention on a neglected disease.Vet Rec. 2007; 161: 288-289Crossref PubMed Scopus (21) Google Scholar]. In this vein, introducing novel control strategies and campaigns that may directly affect the economical status of livestock owners may result in opposition or unwillingness to co-operate by the public, thus cancelling any control effort at the beginning [18Blancou J Chomel BB Belotto A Meslin FX Emerging or re‐emerging bacterial zoonoses: factors of emergence, surveillance and control.Vet Res. 2005; 36: 507-522Crossref PubMed Scopus (64) Google Scholar]. Once more regarding our anthropocentric view of the universe, we tend to forget that humans are a rather late link in the vertebrate evolutionary chain, preceded by numerous existing animal species, as well as certain zoonotic agents [19D'Anastasio R Zipfel B Moggi‐Cecchi J et al.Possible brucellosis in an early hominin skeleton from sterkfontein, South Africa.PLoS ONE. 2009; 4: e6439Crossref PubMed Scopus (51) Google Scholar]. Modern man has in general attempted to overrule nature: modern man may have a lizard as a pet (to remember the aforementioned Jenner quote), may taste all sorts of raw delicacies, imported or in the field, may travel in all sorts of virgin environments to recognize true nature (and its true habitats, which are often zoonotic agents of major morbidity and mortality), may interfere with nature's equilibrium by eliminating wildlife that could serve as an infectious reservoir for domestic animals that man himself located near wildlife, and so on. Essentially it's the human that invades and disrupts nature's equilibrium, and naturally nature fights back. A non-anthropocentric view would thus consider man a true virus of nature, one that the universe tries to eliminate using all sorts of weapons, zoonotic bacteria being its antibodies, and zoonotic viruses its natural killer cells. It is therefore not surprising that the vast majority of infectious disease outbreaks reported in recent decades have been of zoonotic nature or at least of zoonotic origin [20Breithaupt H Fierce creatures.EMBO Rep. 2003; 4: 921-924Crossref PubMed Scopus (7) Google Scholar] (Fig. 1), including the major infectious threats of the 21st century, SARS-CoV, avian influenza, the pandemic 2009 influenza, and the West Nile Virus US outbreak. It is further not surprising that all bar one (smallpox) of the Category A listed potential biological weapons [21Ryan CP Zoonoses likely to be used in bioterrorism.Public Health Rep. 2008; 123: 276-281PubMed Google Scholar] and the majority of the Category B listed biological agents [22Pappas G Panagopoulou P Christou L Akritidis N Category B potential bioterrorism agents: bacteria, viruses, toxins, and foodborne and waterborne pathogens.Infect Dis Clin North Am. 2006; 20: 395-421Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar] are of zoonotic nature. The end of humanity by a zoonotic infectious agent has been a common and increasingly popular scenario in films [23Pappas G Seitaridis S Akritidis N Tsianos E Infectious diseases and cinema: virus hunters and killer microbes.Clin Infect Dis. 2003; 37: 939-942Crossref PubMed Scopus (29) Google Scholar]; the recent outbreaks have demonstrated that it is also a plausible scenario, one which raises the question of whether a zoonotic pathogen will eventually be the human race's nemesis. The recent global outbreaks of novel infectious diseases originating in animal species underline that we should anticipate more such outbreaks in the future. We should further take into account that chronic, currently considered idiopathic, diseases may ultimately be attributed to a zoonotic agent: the typical example here is the constantly evaluated potential relationship between Mycobacterium paratuberculosis and Crohn's disease [24Economou M Pappas G New global map of Crohn's disease: genetic, environmental, and socioeconomic correlations.Inflamm Bowel Dis. 2008; 14: 709-720Crossref PubMed Scopus (148) Google Scholar]. Understanding the complexity of zoonotic infections, and tracing the aetiology of their resurgence back to their roots is far from the concept of surveillance/diagnosis/eradication and elimination campaigns. It is foremost a concept of understanding nature as an organic system within which humans serve as a non-integral part, as a part of a chain that can recycle its integrity by expelling humans. 'The single biggest threat to man's continued dominance on the planet is the virus', commented Joshua Lederberg, PhD, Nobel laureate, as cited in the closing credits of the 1995 film Outbreak: few doubt that such a virus would be of zoonotic origin [25Weissenböck H Hubálek Z Bakonyi T Nowotny N Zoonotic mosquito‐borne flaviviruses: Worldwide presence of agents with proven pathogenicity and potential candidates of future emerging diseases.Vet Microbiol. 2010; 140: 271-280Crossref PubMed Scopus (147) Google Scholar]. The author has no conflicts of interest to declare.