BATS ARE NATURAL RESERVOIRS OF SARS-LIKE CORONAVIRUSES PDF

An ongoing outbreak of Middle East respiratory syndrome coronavirus 2 suggests that this group of viruses remains a key threat and that their distribution is wider than previously recognized. Although bats have been suggested to be the natural reservoirs of both viruses 3 , 4 , 5 , attempts to isolate the progenitor virus of SARS-CoV from bats have been unsuccessful. These viruses are far more closely related to SARS-CoV than any previously identified bat coronaviruses, particularly in the receptor binding domain of the spike protein. Preliminary in vitro testing indicates that WIV1 also has a broad species tropism. Our results provide the strongest evidence to date that Chinese horseshoe bats are natural reservoirs of SARS-CoV, and that intermediate hosts may not be necessary for direct human infection by some bat SL-CoVs.

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The virus replicated in cells derived from human, bat and pig. No civet cells were tested [ 29 ]. However, the exact mechanism by which the zoonotic transmission event to humans occurred is still not clear. This study suggests that camel workers with asymptomatic or mild disease may serve as another route of exposure [ 40 ].

Although camels are thought to be the primary zoonotic reservoir for human transmission, there is strong evidence that bats are the ancestral reservoir host for MERS-CoV [ 24 , 41 , 42 , 43 ]. In addition to emerging highly pathogenic coronaviruses, human coronaviruses that cause the common cold are also thought to have their origins in bats.

A survey of bats in the U. HCoVE also appears to have its origins in bat species. HCoVE, another cause of the common cold, was first identified in and has been circulating in the human population for some time [ 54 ]. HCoVE-related viruses have been found in hipposiderid bats during surveillance studies in Kenya and Ghana [ 53 , 55 ]. In , a novel alphacoronavirus was identified in an outbreak of respiratory disease in alpacas in the US, which is geographically separated from the bat species that harbor HCoVE-like viruses in Africa [ 56 ].

By analyzing more bat, alpaca and human HCoVE and HCoVE-related sequences, evidence of genomic changes that occurred between bat and alpaca HCoVE evolution and subsequently between alpaca and human evolution were identified [ 57 ].

Seropositive camels were more prevalent in the Arabian Peninsula compared to Africa and the earliest seropositive sample was from in a study that looked at samples from to [ 58 ]. These data all support the notion that HCoVE has its ancestral origins in bat species while camelids serve as a more recent zoonotic reservoir for human transmission.

A recent study has shown that HCoVE human strain is incapable of infecting and replicating in cell lines from multiple bat species [ 59 ]. PEDV was detected in Belgium in [ 60 ]. PEDV has since emerged in North America and continues to cause periodic outbreaks that significantly affect producers [ 18 , 62 ]. Multiple PEDV vaccine candidates have been shown to provide varying levels of protection in pigs [ 63 , 64 ].

An effective vaccine may enable control of future PEDV outbreaks along with strict biosecurity practices. We Banerjee and Misra et al. PEDV replication in bat cells has not been extensively studied.

Efforts are focused on designing therapeutics and vaccines to prevent PED in pigs. Zhou et al. None of the human serum samples that were collected from farm workers were positive for antibodies against SADS-CoV [ 9 ]. Bats and Coronavirus Spillover Events Understanding how bats maintain a virus within a population is important for predicting spillover transmission events.

For many viruses with known or suspected bat reservoirs, spillover transmission events typically occur within a defined time frame and location, which corresponds with higher than normal virus levels in the bat reservoir host. In the case of Marburg virus MARV , for example, ecological surveillance data shows a clear biannual spike in the prevalence of MARV positive bats within the Kitaka cave population, which correlates with an increase in the number of juvenile Rousettus aegyptiacus bats due to the biannual birthing cycle.

This pulse of virus positive bats correlates with an increased incidence of human spillover events [ 68 ]. Furthermore, recent experimental data has shown that bats infected with MARV clear infection and maintain long-term immunity.

Studies with Hendra virus have shown that reproductive and nutritional stress can increase the levels of virus in little red flying foxes Pteropus scapulatus [ 70 ]. The increase in virus replication may enhance the chances of a virus spillover. Similar ecological studies need to be undertaken for bats and CoVs.

Other stressors, such as secondary infections, may also affect the relationship between bats and their viruses. A recent study by one of our laboratories Misra et al. A recent study by Anthony et al. During the course of this study, they found that the diversity of coronaviruses was highly associated with the diversity of bat species and this diversity separated into 3 distinct geographical regions, which mirrored the distribution of different species of bats.

The authors report particular associations between bat families and viral sub-clades that suggest co-evolution [ 72 ]. A survey of coronaviruses isolated from bats in Kenya found a high prevalence of coronaviruses in Cardioderma cor, Ediolon helvum, Epomophorus labiatuc, Hipposideros sp.

The phylogenetic analysis of these novel CoVs found a number of cross-species transmission events, although the majority of these events appeared to be transient spillover events [ 53 ].

Indeed, there is strong evidence to suggest that a recombination event occurred between HCoVE-like viruses found in Hipposideros bats and HCoV-NLlike viruses found in Triaenops afer bats, where the gene encoding for the spike protein is more closely related to the HCoVE virus [ 53 ].

Furthermore, the majority of recombination events identified in coronaviruses isolated from bats suggest recombination hotspots around the spike gene [ 53 , 23 ]. In theory, bats could serve as an important reservoir for coronaviruses and coronaviruses with altered host tropism may very well evolve in bats. Although bats are known to harbor a wide variety of coronaviruses, the mechanisms for virus spillover into humans or livestock are widely unknown.

There is evidence that there are seasonal fluctuations in virus replication [ 74 , 75 ], however, the interconnectedness of virus replication rates and virus spillover have not been explored for bats.

Typically, coronaviruses found in bats have or require an intermediate host before spilling over into humans, like what is observed with MERS-CoV and camels. Unlike the amount of information available from studies of other bat viruses such as Nipah, Hendra, Ebola, and Marburg viruses, we know very little, if anything about how coronaviruses are transmitted directly to humans or if direct human transmission does not occur and spillover via an intermediate host is required.

Bat Immune Response to Coronaviruses Bats are known to harbor a wide range of viruses including many that are highly pathogenic in humans. Research to determine the mechanisms by which bats limit disease following virus infection is a relatively new field and can be difficult due to a lack of reagents and the need to develop appropriate in vitro and in vivo systems.

Even with these limitations, a variety of studies have been performed that evaluate the bat immune response to virus infection at the genomics level, in vitro using cell culture systems, and performing experimental infections in vivo.

Of note, very few of these studies are focused on coronavirus infections in bats and are rather centered around henipavirus and filovirus infections. Future studies evaluating the virus-host interactions of bats and coronaviruses, particularly with bat CoV isolates are important in determining why bats serve as important reservoirs for CoVs and how they control infection to limit severe pathological consequences.

Cell Culture Model Systems Multiple studies have elucidated unique adaptations in the antiviral responses of bat cells. The primary bat species being used to study the bat immune response to virus infections in vitro and in vivo are Pteropus alecto black flying fox , Rousettus aegyptiacus Egyptian rousette , and Artibeus jamaicensis Jamaican fruit bat.

Papenfuss et al. A similar number of immune genes were also identified in the transcriptomes of R. This included the expression of canonical pattern recognition receptors including toll-like receptors TLRs 1—10, retinoic acid-inducible gene I RIG-I , and melanoma differentiation associated protein 5 MDA5 [ 76 , 77 ]. Furthermore, genes for different immune cell subsets, T-cell receptors TCRs , cytokines and chemokines, and interferon-related genes were detected, while genes encoding for natural killer NK cell receptors were largely absent.

Work has been done to characterize many of these genes in cell lines derived from various bat species including P. A large amount of interest in bat immune responses has focused specifically on the interferon response. Genomic analysis of the interferon loci has shown species-specific evolution in which P. It has been observed that there may also be species specific differences in the baseline expression of type I IFNs.

The molecular mechanisms that enable the differential expression pattern of IFNs in bats are not known. Thus, it is important to acknowledge that different species of bats may have evolved specific strategies to control viruses that they co-evolved with.

Although it appears that bats have many of the genes that are important for responding to virus infection, how this response compares between human and bat cells is just beginning to be examined.

RNA sensing and subsequent antiviral responses in bat cells have been studied using viruses known to induce an interferon response, such as Sendai virus or Newcastle disease virus or by transfecting a synthetic surrogate of viral double stranded RNA poly I:C [ 80 , 86 , 87 , 88 , 89 , 90 ]. These studies show that bat cells respond to RNA and induce an antiviral response. Many viruses encode proteins that antagonize the host response to infection and dampen the innate antiviral response.

It has previously been shown that the V and W proteins of Nipah and Hendra viruses can inhibit antiviral responses in bat cells, similar to what is observed in human cells [ 90 ]. Coronavirus accessory proteins are dispensable for replication but they play an important role in pathogenesis and virus fitness under the natural environment of a host [ 13 , 91 ]. However, to date, there have been no published studies looking at the role of these accessory proteins in modulating antiviral responses in bat cells.

In addition to studying the role of CoV proteins in antagonizing the antiviral response in bat cells compared to other mammalian cell lines, it is also important to determine how CoVs isolated from bats compare to those isolated from humans. Coronavirus accessory genes have co-evolved with their natural host for optimum functionality [ 91 ] and thus it is important to identify the role of accessory proteins in both their natural and spillover hosts.

To overcome this limitation, reverse genetics systems using the whole genome sequence from CoVs isolated from bats could be generated, propagated and evaluated in both bat and human cell lines [ 96 ]. This would allow researchers to better understand the role of viral proteins in a species-specific context. In vivo Model Systems The vast majority of studies evaluating the bat host response to virus infection has been performed in cell lines.

However, there is a great need to understand what happens during a virus infection in bats in vivo. The ability to study these questions is a daunting task and requires specialized facilities and staff, appropriate species selection especially for CoVs, and generating the necessary reagents. Because of these limitations, only a handful of studies have been performed looking at the in vivo response of bats to virus infection.

In fact, there are only two published studies in which experimental infections in bats using CoVs was performed. The first study was performed in an attempt to rescue a bat CoV isolate. Watanabe et al. To propagate CoVs detected in a lesser dog-faced fruit bat Cynopterus brachyotis , they administered intestinal samples orally to Leschenault rousette bats Rousettus leschenaulti. Virus could be detected by quantitative real-time PCR qPCR on 2 to 5 days after infection and there was an increase in viral RNA while no clinical disease was observed.

Based on these data, the authors reported that this bat CoV replicates in Leschenault rousette bats; however, they were not able to isolate live virus [ 97 ]. This study emphasizes the importance of bat species selection for studying CoVs in bats. Ideally, we would want to study a bat CoV in the same species that it was detected in.

The second study aimed to determine if bats could be infected with MERS-CoV and, if so, what the host response looks like. Munster et al. The authors detected virus shedding in the respiratory and intestinal tracts for 9 days. Although the bats showed evidence of virus replication, no overt signs of disease were observed. A moderate and transient induction of the innate immune response was seen, but there were no signs of inflammation.

This study has not been repeated in an insectivorous bat species. Although several MERS-like viruses have been detected in bats since the study in Jamaican fruit bats, none have been successfully isolated [ 25 , 41 , 47 , 99 ]. Another study focused on looking at species-specific tropism. Widagdo et al. In their study, the authors report that DPP4 in insectivorous bats is primarily detected in the gastro-intestinal GI tract and kidneys, whereas frugivorous bats express DPP4 in the respiratory and GI tracts [ 43 ].

Other studies determined that DPP4 expression in camels is primarily in the upper respiratory tract [ ] whereas DPP4 expression in humans is highest in the lower respiratory tract [ ]. These data suggest that the tissue tropism in bats may be different than that in other mammalian species and that this may dictate the course of disease and disease severity. Implications of Bats as Hosts of CoVs The ability of bats to harbor several different coronaviruses may seem like a mystery, but the same is true for rodents.

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Bat origin of human coronaviruses

Full size table Receptor usage The S protein of coronaviruses is a surface-located trimeric glycoprotein consisting of two subunits: the N-terminal S1 subunit and the C-terminal S2 subunit. The S1 subunit specializes in recognizing and binding to the host cell receptor while the S2 region is responsible for membrane fusion. Compared with the S2, the S1 subunit shows much higher variability [ 20 ]. Owing to its function of receptor binding, the variation in S protein defines in large part the tissue tropism and host range of different coronaviruses [ 21 ]. A loop subdomain aa — that directly contacts with ACE2 was further identified as the receptor-binding motif RBM by crystal structure analysis [ 26 ]. In the RBM, several aa residues were found to be critical for receptor binding and changes in these key residues resulted in different binding efficiency among different SARS-CoV isolates [ 26 — 28 ]. Published results indicated that MERS-CoV can infect and replicate in most cell lines derived from human, non-human primate, bat, swine, goat, horse, rabbit, civet, and camel, but not from mice, hamster, dog, ferret, and cat [ 29 — 36 ].

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