Dynamics of bat-coronavirus interactions: role of innate antiviral responses
Date
2018-08-09
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Thesis
Degree Level
Doctoral
Abstract
Bats are speculated to be reservoirs of several emerging viruses including coronaviruses (CoVs) that cause severe acute respiratory syndrome (SARS), Middle-East respiratory syndrome (MERS), porcine epidemic diarrhea and swine acute diarrhea syndrome. These viruses cause significant disease in humans and agricultural animals. MERS-CoV causes serious disease in humans with a thirty-five percent mortality and has evolved proteins that can effectively suppress an innate antiviral response in human cells. Bats that are naturally or experimentally infected with these or similar viruses do not show apparent signs of disease and the molecular mechanisms of protection are not yet known. My doctoral thesis tested the hypothesis that big brown bat cells have unique adaptations in innate antiviral signaling pathways involved in the control of virus replication and coronavirus-induced inflammatory cytokines. To test this hypothesis, we generated the first commercially available North American bat (Eptesicus fuscus; big brown bat) kidney epithelial cell line. Using this cell line, we were able to demonstrate that big brown bat cells have evolved a unique repressor molecule, c-Rel that can effectively suppress double-stranded RNA (poly(I:C)) mediated expression of a key inflammatory cytokine, tumor necrosis factor alpha (TNF). MERS-CoV is thought to have evolved in insectivorous bats before spilling over to camels and eventually to humans. To further our understanding about bat-coronavirus interactions, we demonstrated that big brown bat cells are resistant to MERS-CoV-mediated subversion of antiviral responses. We determined that interferon regulatory factor 3 (IRF3) plays a critical role in controlling MERS-CoV propagation in big brown bat epithelial cells. Indeed, my doctoral thesis has identified two unique adaptations in big brown bat cells that might allow these bats, and probably other species of bats to successfully co-exist with coronaviruses. My thesis supports the hypothesis that bats function as global reservoirs for emerging coronaviruses by providing definitive examples of adaptations that would allow bats to co-exist with these viruses. Future work from my thesis will focus on adapting some of these antiviral strategies in human cells to control coronavirus-mediated disease in humans.
Description
Keywords
Bats, coronavirus, anti-viral defence responses
Citation
Degree
Doctor of Philosophy (Ph.D.)
Department
Veterinary Microbiology
Program
Veterinary Microbiology