Bats as a model to understand the evolution of coronavirus-host interactions

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Bats play important ecological roles and perform critical functions such as pollination, seed dispersal and pest control. However, recent studies have identified that bats are reservoirs of emerging viruses that causes severe and often fatal disease in livestock and humans. These include ebola and Marburg filoviruses, Nipah and Hendra paramyxoviruses and a diverse range of coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, porcine epidemic diarrhea virus (PEDV) and swine acute diarrhea syndrome coronavirus (SADS-CoV). Interestingly, bats that are naturally or experimentally infected with these viruses do not develop apparent signs of infection or disease. Thus, bats provide an intriguing model to study virus-host interactions. As part of our NSERC Discovery proposal, we aim to establish a long-term research program to study how bat immune systems have evolved to better tolerate infections with emerging viruses that cause severe disease in livestock and humans. We shall study how viruses, such as MERS-CoV, SARS-CoV-2 and bona fide bat borne coronaviruses interact with bat cells and identify protective antiviral factors that are produced by bat cells upon virus infection. Preliminary data from our work suggest that upon virus infection, bat cells induce the expression of novel antiviral genes that are not upregulated in infected human cells, which led us to hypothesize that bats have evolved novel antiviral molecules and processes that are distinct from other mammals. We shall use high throughput approaches to identify differentially expressed genes in infected bat cells. We shall characterize cellular processes and protein-protein interactions that come together to harmoniously execute their antiviral effects in bat cells. Finally, we shall functionally characterize the protective effects of bat antiviral proteins using Eptesicus fuscus bats. Our laboratory (in vitro) to animal model (in vivo) characterization will enable robust identification of molecular factors that have evolved in bats to control virus replication without developing disease. Our study will inform the identification and development of novel therapeutic molecules or drug targets in livestock species and humans to control infections with bat borne viruses, such as coronaviruses. In addition, our research will shed light on molecular factors that regulate virus replication in bats and thus identify critical immunological checkpoints that control virus spill over from bats to other mammals. Knowledge gained from our studies will inform national and global policies around emerging zoonotic diseases. Eptesicus fuscus bats are native to Canada and are naturally persistently infected with a bat coronavirus. Thus, our research outcomes will directly affect Canadian agricultural and wildlife sectors, while also positioning Canada as a world leader in research on bats and bat immunology.