Amidst the emergence of novel viruses infecting humans of zoonotic origin, such as MERS-CoV, Ebola or Influenza Virus H7N9, one of the most important questions is to identify the natural host. The emergence of these viruses as human pathogens lead tot he discovery of bats as a favorable animal reservoir for the emergence of novel viruses only second to rodents. In general, bats have a remarkable species diversity with over 1240 known species and a distribution pattern which covers every place on earth with the exception of the polar regions and a few oceanic islands - thus making them important source for viruses to cross the species barrier. Furthermore, bats are hibernating and roosting in diverse places such as caves, tree cavities, rocks, mines, and buildings or under bridges, which are in close proximity with livestock and humans as well. Dissemination and acquisition of pathogens is aided by the capacity to travel long distances, the formation of large colonies and longevity.
Transmission of viral particles from bats to other mammals can occur -as in the case of rabies- via bites or scratches by infected urine and guano. Indeed, one of the most recently identified Coronaviruses was isolated from guano derived from a bat species found in isolated areas of New Zealand. Other sources of transmitting viruses may be the consumption and handling of undercooked bat meat, a practice still common in parts of Asia, Guam and China.
Besides the ecological and biological traits, bats also possess immunological akin to other mammalians. Similar to other mammalians, some bat species can control viral replication by inducing an antiviral response involving the detection of viral RNA by Pattern Recognition Receptors (PRR) thus as membrane bound Toll-like receptors (TLR) for the detection of ssRNA or dsRNA and/or cytosolic Retinoic Acid Inducible Gene (RIG)-1 like helicases which are homologues of and highly similar to those found in humans or in rodents. The infection of bats with a variety of viruses therefore induces an antiviral response consisting of the activation of the antiviral Interferon response similar to other mammalian species. Indeed, both type I and type III IFN can be found in some bat species whilst absent in others. On exception might be however the infection of bats with DNA viruses since the bat genomes which have been sequenced so far do not encode any members of the PYHIN family of DNA sensing proteins; thus the formation of inflammasomes in these species following viral infection might be impaired. Although this deficiency is not relevant for RNA viruses it might explain the prevalence of bat poxviruses in some bat species.
|Schematic outline of antiviral dsDNA signaling by PYHIN|
In general, asymptomatic or persistent viral shedding in the absence of pathology from bats is reported, indicating that cell mediated immunity might be affected by environmental factors such as hibernation and ecological as well as physiological factors.
Viruses found in bats
Besides Rabies Virus and various members of the Coronaviridae, more than 70 zoonotic viruses have been isolated from various bat species, with the majority non-pathogenic for humans or even to be transmitted to other animals. Zoonotic viruses transmitted from bats include not only Rabies Virus, but also the related Nipah and Hendra Viruses (all of them Lyssaviridae), as well as Ebola Virus and Marburg Virus. In other cases where bats are infected with Alphaviruses, Flaviviruses or Bunya-viruses by arthropods it is not clear if bats are a major natural reservoir and transmit viral particles to other hosts.
Following the SARS epidemic in late 2002 initial results identified palm five cats as the natural reservoir of SARS-CoV which have been sold in areas of China in live animal markets. Subsequent studies however identified bats of the genus Rhinolophus as the natural host of a SARS-like bat CoV. More recently a novel human Coronavirus emerged (named Middle East Respiratory Syndrome (MERS) -CoV), this time in Saudi Arabia, causing more than 500 infections not only in the Middle East but also in Europe and North America with 166 number of deaths. Sequencing of the MERS-CoV genome revealed that the virus descended from a bat Coronavirus. Furthermore, a highly similar MERS-like CoV (BtCoV/PML/Neo zul/RSA/2011) has been isolated from the guano of bats in South Africa (Vespertilionidae spp.), suggesting that bats might be again the natural reservoir for a highly pathogenic Coronavirus. Alas no route of transmission to humans has been identified, although it might be possible that camels (or dromedaries to be specific) or racehorses might be acting as an intermittent host. Although it seems at first that bats indigenous to South Africa are related to the emergence of MERS-CoV, it should be noted that Eptesicus bobrinskoi -a member of the Vespertilionida spp.- has been reported to be indigenous to Oman back in 1968, a finding controversial at the time, and confirmed in 2006. Whilst bat cell lines are only showing a low affinity for MERS-CoV in vitro, it would be interesting to study MERS-CoV in cell lines derived from Eptesicus bobrinskoi and to compare to bat cells infected with the virus isolated in South Africa. Also it might be worthwhile to study the South African bat-CoV in human as well as in camel and horse cell lines. So far however any studies using bat derived CoV are limited since a replication competent virus is not available at the moment.
In 1994 an outbreak of an acute respiratory illness in a humans and horses in Hendra (a suburb of Brisbane/Australia) lead to the discovery of a novel virus, subsequently named Hendra Virus. This outbreak was followed by an outbreak of a respiratory illness on pig farms in Malaysia and Singapore -affecting humans and pigs alike- in 1999, which lead to he isolation of Nipah virus. Both viruses are classified within the genus of the Henipaviridae, family Paramyxoviridae and the order of the Mononegavirales. As such the genome is a non-segmented negative sense ssRNA of 18.2kb in size, encoding for six genes corresponding to six structural proteins. Besides Hendra and Nipah, the Henipaviridae contain a third member, Ceder Virus (CedPV). In contrast to Hendra and Nipah Virus, CedPV has not been associated with any clinical disease yet.
|Schematic of Henipavirus particle|
The natural hosts and reservoirs for Hendra and Nipah Virus alike are probably fruit bats of the genus Pteropus spp. including P. alecto, P. poliocephalus, P. scapulatus, and P. conspicillatus, which are indigenous to parts of Asia, Australia, and islands off the coast of East Africa. The importance of bats as a natural reservoir for Henipavirus has been strengthened by recent reports showing that henipavirus-like viruses circulating in fruit bats (Eidolon helvum) in Africa are able to infect a wide range of cell lines including human, simian and bat cell lines.
Since the central determinate of virus tropism are the glycoproteins located on the virus surface, the finding that the glycoprotein from Henipavirus species distinct from those in Southeast Asia and Australia utilizes the same receptor as Nipah Virus might indicate a zoonotic potential. In contrast to Nipah or Hendra Virus however the African variant does not induce syncytia in simian or human cell lines and only limited syncytia formation can be observed in HypNi/1.1, a bat cell line derived from Hypsignathus monstrosus.
These are just two examples of viruses circulating in bats that have crossed the species barrier in the past and exhibit a tropism for human cells. Other examples which pose a potential risk are Poxviruses or GBV-D, a Flavivirus related to Hepatitis C and GB virus recently isolated from bats in Bangladesh, the role of bats in the emergence of A/H17N10 and A/H18N11 subtypes of Influenza in new world bats, or the isolation of a novel Astrovirus - just to name a few. As these examples show, Virology as a discipline is not dead but still alive! Some of the research cannot be done by Virologists alone, but needs to be done in collaboration with zoologists. One example might be to investigate if the reservoir of the African relative of Nipah Virus, Eidolon helvum, is also native to areas where MERS-CoV is circulating? Indeed, a Bat CoV closely related to MERS-CoV was isolated from Taphozous perforates bats; not only did the colony also contain Eidolon helvum bats (in addition of others) but the colony also lived in close proximity to one patient from Saudi Arabia. Also, the patient reported not have had any contact with bats prior infection suggesting that if he got infected by bats the transmission might be due to contaminated guano and/or urine - in other words, virus shed by bats infected.
It might be a far-fetched scenario, but could it be also possible that MERS-CoV was transmitted from bats to camels and humans? This scenario is less hypothetical than one might think. It is indeed widely assumed that both the Alpha-and Betacoronaviridae are derived from an (extinct?) BtCoV and MERS-CoV related BtCoV have been found in African and European bat populations.
Calisher, C., Childs, J., Field, H., Holmes, K., & Schountz, T. (2006). Bats: Important Reservoir Hosts of Emerging Viruses Clinical Microbiology Reviews, 19 (3), 531-545 DOI: 10.1128/CMR.00017-06
Smith I, & Wang LF (2013). Bats and their virome: an important source of emerging viruses capable of infecting humans. Current opinion in virology, 3 (1), 84-91 PMID: 23265969
Wynne, J., & Wang, L. (2013). Bats and Viruses: Friend or Foe? PLoS Pathogens, 9 (10) DOI: 10.1371/journal.ppat.1003651
Zhang G, Cowled C, Shi Z, Huang Z, Bishop-Lilly KA, Fang X, Wynne JW, Xiong Z, Baker ML, Zhao W, Tachedjian M, Zhu Y, Zhou P, Jiang X, Ng J, Yang L, Wu L, Xiao J, Feng Y, Chen Y, Sun X, Zhang Y, Marsh GA, Crameri G, Broder CC, Frey KG, Wang LF, & Wang J (2013). Comparative analysis of bat genomes provides insight into the evolution of flight and immunity. Science (New York, N.Y.), 339 (6118), 456-60 PMID: 23258410
Schattgen SA, & Fitzgerald KA (2011). The PYHIN protein family as mediators of host defenses. Immunological reviews, 243 (1), 109-18 PMID: 21884171
Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, Latz E, & Fitzgerald KA (2009). AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature, 458 (7237), 514-8 PMID: 19158675
Hoffmann M, Müller MA, Drexler JF, Glende J, Erdt M, Gützkow T, Losemann C, Binger T, Deng H, Schwegmann-Weßels C, Esser KH, Drosten C, & Herrler G (2013). Differential sensitivity of bat cells to infection by enveloped RNA viruses: coronaviruses, paramyxoviruses, filoviruses, and influenza viruses. PloS one, 8 (8) PMID: 24023659
Ithete NL, Stoffberg S, Corman VM, Cottontail VM, Richards LR, Schoeman MC, Drosten C, Drexler JF, & Preiser W (2013). Close relative of human Middle East respiratory syndrome
coronavirus in bat, South Africa. Emerging infectious diseases, 19 (10), 1697-9 PMID: 24050621
Barlan A, Zhao J, Sarkar MK, Li K, McCray PB Jr, Perlman S, & Gallagher T (2014). Receptor variation and susceptibility to middle East respiratory syndrome coronavirus infection. Journal of virology, 88 (9), 4953-61 PMID: 24554656
HARRISON, D. (1968). ON THREE MAMMALS NEW TO THE FAUNA OF OMAN, ARABIA, WITH THE DESCRIPTION OF A NEW SUBSPECIES OF BAT Mammalia, 32 (3) DOI: 10.1515/mamm.19184.108.40.2067
Ithete NL, Stoffberg S, Corman VM, Cottontail VM, Richards LR, Schoeman MC, Drosten C, Drexler JF, & Preiser W (2013). Close relative of human Middle East respiratory syndrome coronavirus in bat, South Africa. Emerging infectious diseases, 19 (10), 1697-9 PMID: 24050621
Cui J, Eden JS, Holmes EC, & Wang LF (2013). Adaptive evolution of bat dipeptidyl peptidase 4 (dpp4): implications for the origin and emergence of Middle East respiratory syndrome coronavirus. Virology journal, 10 PMID: 24107353 Luby, S., Gurley, E., & Hossain, M. (2009). Transmission of Human Infection with Nipah Virus Clinical Infectious Diseases, 49 (11), 1743-1748 DOI: 10.1086/647951
Marsh, G., de Jong, C., Barr, J., Tachedjian, M., Smith, C., Middleton, D., Yu, M., Todd, S., Foord, A., Haring, V., Payne, J., Robinson, R., Broz, I., Crameri, G., Field, H., & Wang, L. (2012). Cedar Virus: A Novel Henipavirus Isolated from Australian Bats PLoS Pathogens, 8 (8) DOI: 10.1371/journal.ppat.1002836
Muleya W, Sasaki M, Orba Y, Ishii A, Thomas Y, Nakagawa E, Ogawa H, Hang'ombe B, Namangala B, Mweene A, Takada A, Kimura T, & Sawa H (2014). Molecular Epidemiology of Paramyxoviruses in Frugivorous Eidolon helvum Bats in Zambia. The Journal of veterinary medical science / the Japanese Society of Veterinary Science, 76 (4), 611-4 PMID: 24389743
Chua KB, Koh CL, Hooi PS, Wee KF, Khong JH, Chua BH, Chan YP, Lim ME, & Lam SK (2002). Isolation of Nipah virus from Malaysian Island flying-foxes. Microbes and infection / Institut Pasteur, 4 (2), 145-51 PMID: 11880045
Lawrence P, Escudero Pérez B, Drexler JF, Corman VM, Müller MA, Drosten C, & Volchkov V (2014). Surface glycoproteins of the recently identified African Henipavirus promote viral entry and cell fusion in a range of human, simian and bat cell lines. Virus research, 181, 77-80 PMID: 24452140
Kruger, N., Hoffmann, M., Weis, M., Drexler, J., Muller, M., Winter, C., Corman, V., Gutzkow, T., Drosten, C., Maisner, A., & Herrler, G. (2013). Surface Glycoproteins of an African Henipavirus Induce Syncytium Formation in a Cell Line Derived from an African Fruit Bat, Hypsignathus monstrosus Journal of Virology, 87 (24), 13889-13891 DOI: 10.1128/JVI.02458-13
Epstein JH, Quan PL, Briese T, Street C, Jabado O, Conlan S, Ali Khan S, Verdugo D, Hossain MJ, Hutchison SK, Egholm M, Luby SP, Daszak P, & Lipkin WI (2010). Identification of GBV-D, a novel GB-like flavivirus from old world frugivorous bats (Pteropus giganteus) in Bangladesh. PLoS pathogens, 6 PMID: 20617167
Chu, D., Poon, L., Guan, Y., & Peiris, J. (2008). Novel Astroviruses in Insectivorous Bats Journal of Virology, 82 (18), 9107-9114 DOI: 10.1128/JVI.00857-08
Tong S, Zhu X, Li Y, Shi M, Zhang J, Bourgeois M, Yang H, Chen X, Recuenco S, Gomez J, Chen LM, Johnson A, Tao Y, Dreyfus C, Yu W, McBride R, Carney PJ, Gilbert AT, Chang J, Guo Z, Davis CT, Paulson JC, Stevens J, Rupprecht CE, Holmes EC, Wilson IA, & Donis RO (2013). New world bats harbor diverse influenza A viruses. PLoS pathogens, 9 (10) PMID: 24130481
De Benedictis P, Marciano S, Scaravelli D, Priori P, Zecchin B, Capua I, Monne I, & Cattoli G (2014). Alpha and lineage C betaCoV infections in Italian bats. Virus genes, 48 (2), 366-71 PMID: 24242847
Nowotny N, & Kolodziejek J (2014). Middle East respiratory syndrome coronavirus (MERS-CoV) in dromedary camels, Oman, 2013. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin, 19 (16) PMID: 24786259
Memish, Z., Mishra, N., Olival, K., Fagbo, S., Kapoor, V., Epstein, J., AlHakeem, R., Durosinloun, A., Al Asmari, M., Islam, A., Kapoor, A., Briese, T., Daszak, P., Al Rabeeah, A., & Lipkin, W. (2013). Middle East Respiratory Syndrome Coronavirus in Bats, Saudi Arabia Emerging Infectious Diseases, 19 (11) DOI: 10.3201/eid1911.131172
Annan A, Baldwin HJ, Corman VM, Klose SM, Owusu M, Nkrumah EE, Badu EK, Anti P, Agbenyega O, Meyer B, Oppong S, Sarkodie YA, Kalko EK, Lina PH, Godlevska EV, Reusken C, Seebens A, Gloza-Rausch F, Vallo P, Tschapka M, Drosten C, & Drexler JF (2013). Human betacoronavirus 2c EMC/2012-related viruses in bats, Ghana and Europe. Emerging infectious diseases, 19 (3), 456-9 PMID: 23622767