Bats as ‘special’ reservoirs for emerging zoonotic pathogens
2015; Elsevier BV; Volume: 23; Issue: 3 Linguagem: Inglês
10.1016/j.tim.2014.12.004
ISSN1878-4380
AutoresCara E. Brook, Andrew P. Dobson,
Tópico(s)Zoonotic diseases and public health
Resumo•Bats experience morbidity to many extracellular but few intracellular infections.•Bats control intracellular pathogens via cellular pathways to apoptosis/autophagy.•These ROS mitigation pathways promote longevity and tumor avoidance.•Extracellular pathogen-associated morbidity in bats results from immunopathology. The ongoing West African Ebola epidemic highlights a recurring trend in the zoonotic emergence of virulent pathogens likely to come from bat reservoirs that has caused epidemiologists to ask 'Are bats special reservoirs for emerging zoonotic pathogens?' We collate evidence from the past decade to delineate mitochondrial mechanisms of bat physiology that have evolved to mitigate oxidative stress incurred during metabolically costly activities such as flight. We further describe how such mechanisms might have generated pleiotropic effects responsible for tumor mitigation and pathogen control in bat hosts. These synergisms may enable 'special' tolerance of intracellular pathogens in bat hosts; paradoxically, this may leave them more susceptible to immunopathological morbidity when attempting to clear extracellular infections such as 'white-nose syndrome' (WNS). The ongoing West African Ebola epidemic highlights a recurring trend in the zoonotic emergence of virulent pathogens likely to come from bat reservoirs that has caused epidemiologists to ask 'Are bats special reservoirs for emerging zoonotic pathogens?' We collate evidence from the past decade to delineate mitochondrial mechanisms of bat physiology that have evolved to mitigate oxidative stress incurred during metabolically costly activities such as flight. We further describe how such mechanisms might have generated pleiotropic effects responsible for tumor mitigation and pathogen control in bat hosts. These synergisms may enable 'special' tolerance of intracellular pathogens in bat hosts; paradoxically, this may leave them more susceptible to immunopathological morbidity when attempting to clear extracellular infections such as 'white-nose syndrome' (WNS). The association between bats and human disease has been acknowledged for over a century, since the first identification of rabies Lyssavirus in asymptomatic vampire bats in 1911 [1Carini A. Sur une grande épizootie de rage.Ann. Inst. Pasteur (Paris). 1911; 25 (in French): 843-846Google Scholar]. Until recently, rabies dominated the scientific literature on bats and disease; however, following the emergence of horse- and human-infecting Hendra virus from Australian flying foxes in 1994 [2Field H.E. et al.A fatal case of Hendra virus infection in a horse in north Queensland: clinical and epidemiological features.Aust. Vet. J. 2000; 78: 279-280Crossref PubMed Scopus (85) Google Scholar], bats have emerged as potential reservoirs (see Glossary) for a broad variety of zoonotic infections involving particularly virulent – and often fatal – RNA viruses. Although isolation of live virus from bat hosts has proven elusive in certain cases – notably that of Ebola [3Leroy E.M. et al.Fruit bats as reservoirs of Ebola virus.Nature. 2005; 438: 575-576Crossref PubMed Scopus (1204) Google Scholar] – major evidence supports the role of bats as reservoirs for Hendra and Nipah henipaviruses, Ebola and Marburg filoviruses, and severe acute respiratory syndrome (SARS) and likely Middle East respiratory syndrome (MERS) coronaviruses (CoVs), as well [4Calisher C.H. et al.Bats: important reservoir hosts of emerging viruses.Clin. Microbiol. Rev. 2006; 19: 531-545Crossref PubMed Scopus (1114) Google Scholar, 5Memish Z.A. et al.Coronavirus in bats, Saudi Arabia.Emerg. Infect. 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Host switching in Lyssavirus history from the Chiroptera to the Carnivora orders.J. Virol. 2001; 75: 8096-8104Crossref PubMed Scopus (310) Google Scholar] and henipaviruses [8Gould A.R. Comparison of the deduced matrix and fusion protein sequences of equine morbillivirus with cognate genes of the Paramyxoviridae.Virus Res. 1996; 43: 17-31Crossref PubMed Scopus (59) Google Scholar]. We explore evolutionary mechanisms enabling this immunological tolerance in bats that may be lacking in non-volant mammals, including humans. Recent studies have confirmed an ancient phylogenetic relationship between bats and a suite of other viral pathogens: in addition to lyssaviruses and henipaviruses, bats are now posited as the most ancestral host taxon for the entire family of paramyxoviruses (of which henipaviruses represent one genus [9Drexler J.F. et al.Bats host major mammalian paramyxoviruses.Nat. 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Dis. 2014; 20: 741-745Crossref PubMed Scopus (237) Google Scholar] and meta-analyses [19Turmelle A.S. Olival K.J. Correlates of viral richness in bats (order Chiroptera).Ecohealth. 2009; 6: 522-539Crossref PubMed Scopus (73) Google Scholar, 20Luis A.D. et al.A comparison of bats and rodents as reservoirs of zoonotic viruses: are bats special?.Proc. R. Soc. B. 2013; 280 (20122753, http://dx.doi.org/10.1098/rspb.2012.2753)Crossref PubMed Scopus (489) Google Scholar] from various perspectives, continually asking 'Are bats special in their reservoir roles for zoonotic pathogens?' Common threads prevail and, increasingly, the consensus seems to be a complex and qualified 'yes'. Although not the most represented mammalian order among zoonotic hosts, bats host more zoonotic viruses per species than do rodents and most of the resulting zoonoses have been high-profile spillover incidents of extreme human pathogenicity [21Dobson A.P. What links bats to emerging infectious diseases?.Science. 2005; 310: 628-629Crossref PubMed Scopus (127) Google Scholar]. Bats largely host viral pathogens without demonstrating ostensible disease [22Baker M.L. et al.Antiviral immune responses of bats: a review.Zoonoses Public Health. 2013; 60: 104-116Crossref PubMed Scopus (176) Google Scholar], but the pathogenicity is complex and research into impacts of viral infection on bat fitness, particularly with respect to fecundity or longevity, has been critically lacking. Obvious exceptions to viral asymptomaticity in bats include, notably, rabies and Tacaribe virus, a South American Arenavirus that caused widespread bat mortality in the 1950s and in later experimental infections [23Cogswell-Hawkinson A. et al.Tacaribe virus causes fatal infection of an ostensible reservoir host, the Jamaican fruit bat.J. Virol. 2012; 86: 5791-5799Crossref PubMed Scopus (58) Google Scholar]. Adenoviruses have also been linked to bat mortality [24Sonntag M. et al.New adenovirus in bats, Germany.Emerg. Infect. Dis. 2009; 15: 2052-2055Crossref PubMed Scopus (65) Google Scholar], although such patterns are perhaps unsurprising given the disparity between this gastrointestinal system-infecting DNA virus and other bat-affiliated (mostly RNA) viruses discussed here. One study demonstrated seasonal amplification of RNA viruses, but not DNA viruses, in a monitored insectivorous bat colony in Europe [25Drexler J.F. et al.Amplification of emerging viruses in a bat colony.Emerg. Infect. Dis. 2011; 17: 449-456Crossref PubMed Scopus (163) Google Scholar], suggesting that different mechanisms of control may be at play for RNA versus DNA viruses in bat hosts. Additionally, a novel filovirus, Lloviu virus, was recently detected in bat tissues following a massive die-off event [26Maruyama J. et al.Characterization of the envelope glycoprotein of a novel filovirus, Lloviu virus.J. Virol. 2014; 88: 99-109Crossref PubMed Scopus (79) Google Scholar], and although originally cited as the cause of bat mortality Lloviu virus has now been resolved to be a uniquely bat-adapted virus, leading researchers to explore other mechanisms for bat mortality in this incident [27Olival K. Hayman D. Filoviruses in bats: current knowledge and future directions.Viruses. 2014; 6: 1759-1788Crossref PubMed Scopus (217) Google Scholar]. In one study examining causes of mortality in 486 deceased bats in Europe, viral infections (lyssaviruses and adenoviruses) were responsible for only five of 144 identified disease-related deaths [28Mühldorfer K. et al.Diseases and causes of death in European bats: dynamics in disease susceptibility and infection rates.PLoS ONE. 2011; 6: e29773Crossref PubMed Scopus (79) Google Scholar]. Recent work has begun to investigate the role of bats as hosts for non-viral pathogens, with somewhat varied results. Similar to viruses, bats demonstrate coevolutionary associations with intracellular malarial protozoa [29Schaer J. et al.High diversity of West African bat malaria parasites and a tight link with rodent Plasmodium taxa.Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 17415-17419Crossref PubMed Scopus (102) Google Scholar] as well as extracellular trypanosome protozoa including Trypanosoma cruzi, the causative agent in zoonotic Chagas disease [30Hamilton P.B. et al.The evolution of Trypanosoma cruzi: the "bat seeding" hypothesis.Trends Parasitol. 2012; 28: 136-141Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar]. Bats also exhibit coevolutionary specificity with erythrocytic Bartonella spp. bacteria [31Kosoy M. et al.Bartonella spp. in bats, Kenya.Emerg. Infect. Dis. 2010; 16: 1875-1881Crossref PubMed Scopus (89) Google Scholar]. On a par with viruses, bats appear to host both classes of protozoa and Bartonella spp. without ostensible disease symptoms, yet they exhibit pronounced pathology following infection with certain extracellular pathogens, chiefly Borellia spp. [32Evans N.J. et al.Fatal borreliosis in bat caused by relapsing fever spirochete, United Kingdom.Emerg. Infect. Dis. 2009; 15: 1330-1331Crossref PubMed Scopus (14) Google Scholar] and some enteric bacteria [33Mühldorfer K. Bats and bacterial pathogens: a review.Zoonoses Public Health. 2013; 60: 93-103Crossref PubMed Scopus (183) Google Scholar]. Bats also experience pathology on infection with the bacterium Pasteurella multocida [34Blehert D.S. et al.Acute pasteurellosis in wild big brown bats (Eptesicus fuscus).J. Wildl. Dis. 2014; 50: 136-139Crossref PubMed Scopus (12) Google Scholar], which can function as both an intra- and extracellular pathogen. Table 1 summarizes bat-hosted pathogens by clade and offers examples to illustrate what is currently known of their affiliated pathogenicity.Table 1Example bat infections and associated immune responses across microbial classesMicrobial classExample pathogenInfection siteDocumented pathology in bat host?RefsVirusesHenipavirus spp.Intracellular (blood + tissue)No88Halpin K. et al.Pteropid bats are confirmed as the reservoir hosts of henipaviruses: a comprehensive experimental study of virus transmission.Am. J. Trop. Med. Hyg. 2011; 85: 946-951Crossref PubMed Scopus (293) Google ScholarLyssavirus spp.Intracellular (central nervous system)Yes (pathogen induced)46Turmelle A.S. et al.Host immunity to repeated rabies virus infection in big brown bats.J. Gen. Virol. 2010; 91: 2360-2366Crossref PubMed Scopus (92) Google Scholar, 57Wang Z.W. et al.Attenuated rabies virus activates, while pathogenic rabies virus evades the host innate immune responses in the central nervous system.J. Virol. 2005; 79: 12554-12565Crossref PubMed Scopus (213) Google ScholarBacteriaBartonella spp.Intracellular (blood + tissue)No31Kosoy M. et al.Bartonella spp. in bats, Kenya.Emerg. Infect. Dis. 2010; 16: 1875-1881Crossref PubMed Scopus (89) Google ScholarBorellia spp.Extracellular (blood)Yes32Evans N.J. et al.Fatal borreliosis in bat caused by relapsing fever spirochete, United Kingdom.Emerg. Infect. Dis. 2009; 15: 1330-1331Crossref PubMed Scopus (14) Google ScholarProtozoaPlasmodium spp.Intracellular (blood + tissue)No29Schaer J. et al.High diversity of West African bat malaria parasites and a tight link with rodent Plasmodium taxa.Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 17415-17419Crossref PubMed Scopus (102) Google ScholarTrypanosoma spp.Extracellular (blood with intracellular amastigote stage)No30Hamilton P.B. et al.The evolution of Trypanosoma cruzi: the "bat seeding" hypothesis.Trends Parasitol. 2012; 28: 136-141Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 42Cabral H.R.A. The tumoricidal effect of Trypanosoma cruzi: its intracellular cycle and the immune response of the host.Med. Hypotheses. 2000; 54: 1-6Abstract Full Text PDF PubMed Scopus (21) Google ScholarFungiHistoplasma capsulatumIntracellular (macrophage)No (except experimental manipulation)40Greer D.L. McMurray A.N. Pathogenesis of experimental histoplasmosis in the bat, Artibeus lituratus.Am. J. Trop. Med. Hyg. 1981; 30: 653-659PubMed Google ScholarPseudogymnoascus destructansExtracellular (wing surface)Yes (immunopathology)41Meteyer C.U. et al.Pathology in euthermic bats with white nose syndrome suggests a natural manifestation of immune reconstitution inflammatory syndrome.Virulence. 2012; 3: 1-6Crossref PubMed Scopus (89) Google ScholarHelminthLecithodendrium spp.Extracellular (intestine)Minimal35Lord J.S. et al.Gastrointestinal helminths of pipistrelle bats (Pipistrellus pipistrellus/Pipistrellus pygmaeus) (Chiroptera: Vespertilionidae) of England.Parasitology. 2012; 139: 366-374Crossref PubMed Scopus (31) Google Scholar Open table in a new tab In addition to supporting microparasitic viruses, protozoa, and bacteria, bats are hosts for various macroparasitic helminths, chiefly trematodes [35Lord J.S. et al.Gastrointestinal helminths of pipistrelle bats (Pipistrellus pipistrellus/Pipistrellus pygmaeus) (Chiroptera: Vespertilionidae) of England.Parasitology. 2012; 139: 366-374Crossref PubMed Scopus (31) Google Scholar], nematodes (including some filarial species [36Lichtenfels J.R. et al.Filaroid nematodes in olfactory mucosa, olfactory bulb, and brain ventricular system of bats.Trans. Am. Microsc. Soc. 1981; 100: 216-219Crossref Google Scholar]), and cestodes [37Ubelaker J.E. Some observations on ecto- and endoparasites of Chiroptera.in: Slaughter B.H. Walton D.W. About Bats. Southern Methodist University Press, 1970: 247-261Google Scholar]. Bat susceptibility to helminths appears consistent with that of other mammals, which exhibit dose-dependent morbidity rather than mortality. Curiously, some hibernating bats display idiosyncratic patterns of helminth retention that differ from typical patterns of voidance during hibernation in other mammals [38Coggins J.R. et al.Seasonal changes and overwintering of parasites in the bat, Myotis lucifugus (Le Conte) in a Wisoconsin hibernaculum.Am. Midl. Nat. 1982; 107: 305-315Crossref Scopus (21) Google Scholar]. Bats have also been long recognized as sources of the globally distributed zoonotic fungus Histoplasma capsulatum, which, as an intracellular parasite of macrophages [39Sebghati T.S. Intracellular parasitism by Histoplasma capsulatum: fungal virulence and calcium dependence.Science. 2000; 290: 1368-1372Crossref PubMed Scopus (149) Google Scholar], is asymptomatic in the chiropteran host. By contrast, when experimentally introduced via intraperitoneal inoculation, the pathogen overwhelms the extracellular spaces of bat tissues, causing lesions and severe inflammation [40Greer D.L. McMurray A.N. Pathogenesis of experimental histoplasmosis in the bat, Artibeus lituratus.Am. J. Trop. Med. Hyg. 1981; 30: 653-659PubMed Google Scholar]. This pronounced immunopathological response to fungal infection is particularly germane to the current widespread infection of North American bats with the extracellular fungus Pseudogymnoascus destructans (the causative agent of WNS). Histological wing lesions characteristic of WNS suggest massive immunopathological inflammation when hibernating bats infected with P. destructans arouse from torpor [41Meteyer C.U. et al.Pathology in euthermic bats with white nose syndrome suggests a natural manifestation of immune reconstitution inflammatory syndrome.Virulence. 2012; 3: 1-6Crossref PubMed Scopus (89) Google Scholar]. Thus, the ubiquitous role of bats as special pathogen reservoirs is called into question when pathogens beyond the 'virosphere' are considered; bats exhibit standard-to-extreme pathology following infection with certain bacteria and fungi. In particular, this comparison highlights the unique resilience of bats to infection with intracellular pathogens – a category encompassing all viruses, some protozoa, and some bacteria. By contrast, pathogens that predominantly occupy the extracellular space present considerable challenges for bat immune systems. In the case of trypanosomes, it should be noted that, although largely extracellular, trypanosomes also support an intracellular, amastigote life stage that is subject to the majority of immunological attack and regulation [42Cabral H.R.A. The tumoricidal effect of Trypanosoma cruzi: its intracellular cycle and the immune response of the host.Med. Hypotheses. 2000; 54: 1-6Abstract Full Text PDF PubMed Scopus (21) Google Scholar]. In the following sections, we explore unique mechanisms linking immune functioning with bat metabolism and longevity to offer a new explanation for how bat physiology and immunology enable a special reservoir role for viral pathogens. Like other mammals, bat immune systems comprise both innate and adaptive elements (Figure 1) [22Baker M.L. et al.Antiviral immune responses of bats: a review.Zoonoses Public Health. 2013; 60: 104-116Crossref PubMed Scopus (176) Google Scholar]. The first line of innate immune defense involves classification of pathogens into broad microbial categories by pattern recognition receptors (PRRs), typically localized in dendritic cells, that enable the host to mount a pathogen-appropriate immune response (Box 1) [43Palm N.W. Medzhitov R. Pattern recognition receptors and control of adaptive immunity.Immunol. Rev. 2009; 227: 221-233Crossref PubMed Scopus (581) Google Scholar]. PRRs are well conserved between bats and other mammalian lineages and the bat immune system capably detects a broad range of viruses, bacteria, and fungi [44Cowled C. et al.Molecular characterisation of Toll-like receptors in the black flying fox Pteropus alecto.Dev. Comp. Immunol. 2011; 35: 7-18Crossref PubMed Scopus (56) Google Scholar]. PRR detection of foreign microbes produces a cascade of cytokine signaling specific to the class of microbe encountered. These cytokines serve as signaling molecules for cell-mediated components of the innate immune system [i.e., recruitment of phagocytic neutrophils and monocytes and cytotoxic natural killer (NK) cells] and drive T cell differentiation in the adaptive immune system. In the humoral immune system, the body's complement cascade constitutes the main innate immune component, while B lymphocytes, their daughter plasma cells, and the antibodies they synthesize represent the adaptive component.Box 1Pathogen recognition, host immune defense, and the mitochondriaTransmembrane versus cytosolic PRRsPRRs located within the cellular membrane are capable of recognizing both intra- and extracellular pathogens, while cytosolic PRRs are generally restricted to recognition of intracellular pathogens, chiefly viruses or bacteria [43Palm N.W. Medzhitov R. Pattern recognition receptors and control of adaptive immunity.Immunol. Rev. 2009; 227: 221-233Crossref PubMed Scopus (581) Google Scholar]. Transmembrane Toll-like receptors (TLRs) have long been acknowledged for their viral recognition role in the mammalian immune system, but the discovery of a new class of cytosolic PRR, the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), offers an alternative pathway implicated in the immune recognition of RNA viruses [89Koyama S. et al.Differential role of TLR- and RLR-signaling in the immune responses to influenza A virus infection and vaccination.J. Immunol. 2007; 179: 4711-4720Crossref PubMed Scopus (253) Google Scholar].Pathogen recognition and cytokine inductionIn humans, pathogen recognition via TLRs induces cytokines such as IL-12, which recruit neutrophils and monocytes of the innate immune system and stimulate the Th1 branch of the cell-mediated components of the adaptive immune system. Pathogen (usually virus) recognition by RLRs also upregulates Th1 pathways of adaptive immunity, but does so through induction of the cytokine IFN-γ, which favors NK cell routes of innate immunity. By contrast, extracellular fungi are detected at dectin-1 PRRs that induce IL-23, the cytokine responsible for upregulation of the Th17 branch of cell-mediated adaptive immunity [43Palm N.W. Medzhitov R. Pattern recognition receptors and control of adaptive immunity.Immunol. Rev. 2009; 227: 221-233Crossref PubMed Scopus (581) Google Scholar].A role for the mitochondriaIntriguingly, RLR signaling appears to require the participation of a protein (MAVS) bound in the outer membrane of the cellular mitochondria, thus necessitating a role for mitochondria in viral immunity. Mitochondria have long been recognized for their role in general cell maintenance, damage repair, and apoptosis, a process initiated by PRR recognition of damage-associated molecular patterns (DAMPs), which include mitochondrial ROS. PRRs recognize and respond to pathogen-associated molecular patterns (PAMPs) in a similar way [90West A.P. et al.Mitochondria in innate immune responses.Nat. Rev. Immunol. 2011; 11: 389-402Crossref PubMed Scopus (995) Google Scholar]. With the recent discovery of RLRs and their localization to the mitochondria, awareness of the underappreciated role of the mitochondria in immune function is growing. Transmembrane versus cytosolic PRRs PRRs located within the cellular membrane are capable of recognizing both intra- and extracellular pathogens, while cytosolic PRRs are generally restricted to recognition of intracellular pathogens, chiefly viruses or bacteria [43Palm N.W. Medzhitov R. Pattern recognition receptors and control of adaptive immunity.Immunol. Rev. 2009; 227: 221-233Crossref PubMed Scopus (581) Google Scholar]. Transmembrane Toll-like receptors (TLRs) have long been acknowledged for their viral recognition role in the mammalian immune system, but the discovery of a new class of cytosolic PRR, the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), offers an alternative pathway implicated in the immune recognition of RNA viruses [89Koyama S. et al.Differential role of TLR- and RLR-signaling in the immune responses to influenza A virus infection and vaccination.J. Immunol. 2007; 179: 4711-4720Crossref PubMed Scopus (253) Google Scholar]. Pathogen recognition and cytokine induction In humans, pathogen recognition via TLRs induces cytokines such as IL-12, which recruit neutrophils and monocytes of the innate immune system and stimulate the Th1 branch of the cell-mediated components of the adaptive immune system. Pathogen (usually virus) recognition by RLRs also upregulates Th1 pathways of adaptive immunity, but does so through induction of the cytokine IFN-γ, which favors NK cell routes of innate immunity. By contrast, extracellular fungi are detected at dectin-1 PRRs that induce IL-23, the cytokine responsible for upregulation of the Th17 branch of cell-mediated adaptive immunity [43Palm N.W. Medzhitov R. Pattern recognition receptors and control of adaptive immunity.Immunol. Rev. 2009; 227: 221-233Crossref PubMed Scopus (581) Google Scholar]. A role for the mitochondria Intriguingly, RLR signaling appears to require the participation of a protein (MAVS) bound in the outer membrane of the cellular mitochondria, thus necessitating a role for mitochondria in viral immunity. Mitochondria have long been recognized for their role in general cell maintenance, damage repair, and apoptosis, a process initiated by PRR recognition of damage-associated molecular patterns (DAMPs), which include mitochondrial ROS. PRRs recognize and respond to pathogen-associated molecular patterns (PAMPs) in a similar way [90West A.P. et al.Mitochondria in innate immune responses.Nat. Rev. Immunol. 2011; 11: 389-402Crossref PubMed Scopus (995) Google Scholar]. With the recent discovery of RLRs and their localization to the mitochondria, awareness of the underappreciated role of the mitochondria in immune function is growing. Until recently, most insights into bat immunity were derived from studies measuring humoral adaptive immune responses, mainly because the tools for antibody detection are available [16Hayman D.T.S. et al.Ecology of zoonotic infectious diseases in bats: current knowledge and future directions.Zoonoses Public Health. 2013; 60: 2-21Crossref PubMed Scopus (141) Google Scholar]. Bats do mount antibody responses to various infections, including lyssaviruses, filoviruses, and henipaviruses, but these responses are sometimes idiosyncratic [16Hayman D.T.S. et al.Ecology of zoonotic infectious diseases in bats: current knowledge and future directions.Zoonoses Public Health. 2013; 60: 2-21Crossref PubMed Scopus (141) Google Scholar]. In particular, antibody recruitment has been demonstrated to be delayed post-immune challenge in bat cells compared with other vertebrates [45Chakraborty A.K. Chakravarty A.K. Dichotomy of lymphocyte population and cell-mediated immune responses in a fruit bat.J. Ind. Inst. Sci. 1983; 64: 157-168Google Scholar] and repeated rabies inoculations over a longitudinal time series produce a discontinuous pattern of adaptive immunity in which antibodies in seemingly immune bats sometimes drop below detectable levels altogether or virus and antibody (but not disease) are detected concurrently [46Turmelle A.S. et al.Host immunity to repeated rabies virus infection in big brown bats.J. Gen. Virol. 2010; 91: 2360-2366Crossref PubMed Scopus (92) Google Scholar]. Other work demonstrates heightened seroprevalence in female bats during periods of pregnancy and lactation with waning antibodies across the rest of the year, as well as heightened seroprevalence in bats of both sexes under nutritionally stressed conditions [47Plowright R.K. et al.Reproduction and nutritional stress are risk factors for Hendra virus infection in little red flying foxes (Pteropus scapulatus).Proc. R. Soc. B. 2008; 275: 861-869Crossref PubMed Scopus (230) Google Scholar]. These findings suggest that bats may exhibit increased reliance on adaptive immunity when normal immunological pathways used to control infections are otherwise compromised. As heightened viral shedding and concomitant spillover events have been linked to bat reproduction for both henipaviruses and filoviruses [47Plowright R.K. et al.Reproduction and nutritional stress are risk factors for Hendra virus infection in little red flying foxes (Pteropus scapulatus).Proc. R. Soc. B. 2008; 275: 861-869Crossref PubMed Scopus (230) Google Scholar, 48Amman B.R. et al.Seasonal pulses of Marburg virus circulation in juvenile Rousettus aegyptiacus bats coincide with periods of increased risk of human infection.PLoS Pathog. 2012; 8: e1002877Crossref PubMed Scopus (289) Google Scholar], it is possible that humoral adaptive immunity is less effective at controlling viral transmission than bats' standard mechanism of immune regulation. In the realm of cell-mediated immun
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