Investigating the role of accessory protein ORF8 secretion and immunomodulation in the pathogenesis of SARS-CoV-2 and its variants

The COVID-19 pandemic caused by SARS-CoV-2 continues to have devastating global impacts. While vaccines and treatments have been developed and its high transmissibility and severe disease outcomes have been extensively explored, our knowledge of the underlying viral and cellular mechanisms is lacking. Moreover, the ongoing emergence of new SARS-CoV-2 variants like Omicron compromise efforts to limit COVID-19 spread. Common to all variants are sets of naturally selected changes that enable increased viral spread and immune escape. Notably, one of the most rapidly changing viral components is Open Reading Frame (ORF) 8, the only known secreted viral protein whose presence in COVID-19 patients' blood has been linked to disease severity and mortality. ORF8 possesses unique properties allowing it to interfere with the immune system, including suppressing key components for immune detection of virus infection; I discovered that ORF8 downregulates Fcg receptors (FcgRs) found on immune cells that associate with antiviral antibodies to protect against infection. However, it remains poorly understood how ORF8 functions in SARS-CoV-2 variants and how it exits infected cells to exert its effects. I therefore hypothesize that ORF8 release contributes significantly to viral immune escape, including its suppression of FcgRs, and that changes to ORF8 may modulate the transmission and pathogenesis of SARS-CoV-2 variants by enhancing its release and immune modulation capabilities. This work has three main aims: first, to identify changes in ORF8 among SARS-CoV-2 variants; second, to investigate ORF8 functions in immune modulation, including FcgR antagonization, and how these vary in SARS-CoV-2 variants and; third, to determine how ORF8 exits infected cells. Such work promises insights into crucial pathogenic strategies employed by SARS-CoV-2, and will inspire the development of antiviral therapies specifically targeting immune impairment to save lives of SARS-infected individuals.