SHINING A LIGHT ON BAT CELLULAR IMMUNITY FOLLOWING VIRUS INFECTION

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Project summary/abstract Bats are important reservoir hosts for a variety of viruses, several of which are associated with fatality rates as high as 90% among diagnosed human cases. This includes the highly pathogenic henipaviruses, of which Hendra virus (HeV) emerged in Australia and Nipah virus (NiV) in South-east Asia via horse and pig intermediate hosts respectively. The henipaviruses have been shown to be transmitted from Pteropus bats, with the Australian black flying fox (Pteropus alecto) confirmed as a reservoir for HeV (1, 2). As with other viral infections in bats, natural or experimental infection of bats with HeV causes no clinical signs of disease despite shedding of virus. The antiviral immune response of P. alecto is among the most well studied of all bat species, with novel immune mechanisms already discovered including the constitutive expression of interferon alpha discovered by our team (3). These characteristics make the P. alecto – HeV model uniquely suited to answering the questions we propose in this project. Despite the increasing emergence of zoonotic viruses from bats, studies of bat immunology remain in their infancy and few studies have examined the adaptive immune responses of any bat species. Understanding the antiviral responses in bats is crucial if we are to predict and prevent virus spillover from bats to other susceptible species, understand disease pathogenesis in other mammals and uncover new therapeutics and vaccines to treat these diseases in humans and other animals. In this study, we will characterise the innate and adaptive immune response of experimentally infected bats to HeV to obtain detailed insights into how bats control viral infection. The cell mediated immune response of bats will be dissected using functional assays to determine the subsets of cells activated during an active infection and explore global gene and protein expression to characterise the innate and adaptive immune response of infected bats. The use of innovative approaches to identify MHC bound HeV peptides in infected bats, building on previous bat immunopeptidomics studies, will provide new insights into peptide presentation during infection. Few studies have comprehensively studied the immune response of bats during infection, and none have examined the functional activation of the cell mediated immune response. Comparison with infected ferrets will allow us to directly compare mechanisms responsible for innocuous (bats) compared to fatal (ferrets) HeV infection. Expected outcomes include understanding the basic biology of antiviral responses in bats and the development of new tools to monitor bat immunity to HeV and related viruses. The Australian Centre for Disease Preparedness and Monash University are uniquely suited for performing the work outlined in this proposal with a strong track record of working together on bat immunology. The team has access to high containment facilities and expertise to perform animal infections with dangerous pathogens combined with access to protein chemistry facilities and expertise in generating tetramer reagents.