University of North Carolina at Chapel Hill Graduate School
Doi
Abstract
RNA viruses pose a serious global health threat as evidenced by the emergence of SARS-CoV-2 and the COVID-19 pandemic. Three coronaviruses (CoVs) have jumped into the human population over the past two decades: SARS-CoV in 2002, MERS-CoV in 2012, and SARS-CoV-2 in 2019. The potential for future CoV emergence is underappreciated. Bats serve as a reservoir for diverse coronaviruses that may spill over into humans, but it is unclear what fraction of these viruses are capable of infecting humans. Prior to the COVID-19 pandemic, there were no specific antivirals or vaccines for human CoVs, and due to antigenic diversity of bat CoVs, it is unclear if COVID-19 vaccines will prevent future outbreaks. Here we develop models to understand pre-emergent CoVs and recently emergent SARS-CoV-2. We investigated the potential for a bat reservoir MERS-CoV-like virus, PDF-2180, for human emergence. CoV entry into host cells is dependent on interaction with cellular surface receptors and CoV spike protein processing by host proteases. Traditionally the host range restriction for CoVs has been thought to be limited to spike-receptor interactions. Initially not predicted to infect human cells, we identified that PDF-2180 could infect human cells but required exogenous trypsin protease, independently of the MERS-CoV receptor, DPP4. This showed that with adaptation for efficient protease processing, PDF-2180 has the potential for human infection.COVID-19 revealed the need for laboratory models to understand SARS-CoV-2 and develop medical countermeasures. Unlike SARS-CoV, early clinical isolates of SARS-CoV-2 could not infect mice due to incompatibilities with the mouse ortholog of the receptor, ACE2. Here, we developed two mouse-adapted strains of SARS-CoV-2: ‘MA’ and ‘MA10’. SARS-CoV-2 MA10 is a highly pathogenic strain that very closely resembles COVID-19 seen in humans. We use these models to understand SARS-CoV-2 infection and pathogenesis, as well as preclinically test numerous monoclonal antibody therapies, antivirals, and vaccines including Moderna’s mRNA-1273. We also elucidate the mechanisms of long term sequelae in mice to understand ‘long-COVID’ or ‘post-acute sequelae of COVID-19’ seen in human COVID-19 survivors. Altogether, these models will continue to answer unknowns of COVID-19 and develop medical countermeasures for ongoing and future CoV pandemics.Doctor of Philosoph
