Project 467088

The global spread of SARS-CoV-2 has led to significant viral evolution. A number of variants of concern (VOCs) have already been identified, among which Delta now dominates the COVID-19 landscape in many countries including Canada. Common to all VOCs are sets of naturally selected changes providing a fitness advantage for the virus. One of the fastest evolving sites is Open Reading Frame (ORF) 8, a protein present in COVID-19 patients blood whose numerous roles include contributing to cytokine storm seen in severe disease. ORF8 also mediates viral immune escape by downregulating key molecules necessary for immune cells to detect infection. One such molecule is Major Histocompatibility Complex I (MHC-I), a key player in clearing infections by presenting viral components on infected cells to then be targeted by immune cells. Also, I recently discovered that ORF8 downregulates Fc gamma receptor 1A (FcGR1A) present on immune cells that associates with antiviral antibodies to protect against infection. This reduction in MHC-1 and FcGR1A levels lets SARS-CoV-2 evade host immunity, yet whether this function is enhanced in VOCs is unknown. I therefore hypothesize that ORF8 mutations antagonizing immunity through MHC-1 and FcGR1A downregulation contribute to the increased pathogenesis of SARS-CoV-2 VOCs. This work aims to identify mutations enhanced in ORF8 of circulating VOCs and examine if and how they increasingly downregulate MHC-1 and FcGR1A in a cell model system. I believe the characterization of mutations in fast evolving sites like ORF8 is crucial to further elucidate the molecular basis for viral pathogenesis. Such work will inspire the development of antiviral therapies specifically targeting immune impairment to enhance SARS-CoV-2 surveillance by host immunity.