Contribution of SARS-CoV-2 Accessory Proteins to Viral Pathogenicity in K18 Human ACE2 Transgenic Mice
Jesus A. Silvas, Desarey Morales Vasquez, Jun‐Gyu Park, Kevin Chiem, Anna Allué‐Guardia, Andreu Garcia‐Vilanova, Roy N. Platt, Lisa Miorin, Thomas Kehrer, Anastasija Čupić, Ana S. Gonzalez‐Reiche, Harm van Bakel, Adolfo García‐Sastre, Tim Anderson, Jordi B. Torrelles, Chengjin Ye, Luis Martínez‐Sobrido
Abstract
Despite great efforts put forward worldwide to combat the current coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a human health and socioeconomic threat. Insights into the pathogenesis of SARS-CoV-2 and the contribution of viral proteins to disease outcome remain elusive. Our study aims (i) to determine the contribution of SARS-CoV-2 accessory open reading frame (ORF) proteins to viral pathogenesis and disease outcome and (ii) to develop a synergistic platform combining our robust reverse-genetics system to generate recombinant SARS-CoV-2 constructs with a validated rodent model of infection and disease. We demonstrate that SARS-CoV-2 ORF3a and ORF6 contribute to lung pathology and ultimately disease outcome in K18 hACE2 transgenic mice, while ORF7a, ORF7b, and ORF8 have little impact on disease outcome. Moreover, our combinatory platform serves as a foundation for generating attenuated forms of the virus to develop live attenuated vaccines for the treatment of SARS-CoV-2.