The next pandemic? Establishing an experimental framework for assessing virus zoonotic potential using coronaviruses of rodents and humans

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The COVID-19 pandemic has been a stark reminder of the risks that zoonotic virus transmission can pose to humans. Although SARS- CoV-2 and pathogenic predecessors SARS-CoV and MERS-CoV are believed to have origins in bats, other medically important human coronaviruses (CoVs), namely OC43 and HKU1, are widely believed to have rodent origins. Thus, while significant recent research has focused on the origins and zoonotic potential of CoVs in bats, those in rodents remain more poorly understood. To this end, although dozens of CoVs have been identified in diverse rodent species since 2015, our knowledge of these viruses is almost entirely in silico (sequence-based). There is therefore an urgent need to undertake experimental investigations that will provide a better understanding of the pandemic potential of CoVs in rodents, particularly in light of their peri-domestic/peri-urban nature. Moreover, this propensity for humans and rodents to share space also highlights the equally urgent need to understand whether rodents might serve as reservoirs for human CoVs.The work proposed here will thus investigate the potential for, and determinants of, CoV transmission between rodents and humans, using 4 primary objectives:1. Evaluate the capacity for zoonotic transmission of rodent CoVs to humans2. Determine the capacity of human CoVs to establish reservoirs in rodents3. Identify specific molecular barriers that govern transmission of CoVs between humans and rodents 4. Generate computational predictions of CoV transmission risks between humans and rodentsTo achieve these aims, the fellowship will incorporate diverse and ambitious molecular and computational approaches and bridge in vitro and in vivo experimentation. Ultimately this will not only elucidate CoV cross-species transmission risks but establish an experimental framework for more broadly evaluating virus zoonotic and pandemic potential.