Investigating the Antagonization of IgA-Mediated Mucosal Immunity by the SARS-CoV-2 Accessory Protein ORF8

Causing over 6.6 million deaths since its emergence in 2019, SARS-CoV-2 continues to threaten global health despite the development of effective vaccines that have mitigated disease severity. Although current intramuscular immunization regimens mediate decreased symptomatic disease, their capacity to prevent asymptomatic viral spread and infection is limited. As a result, mucosal vaccine development has been initiated in hopes of generating an immune response directly in the lung mucosa to prevent the establishment of infection and restrict SARS-CoV-2 spread. To this end, it is essential to understand the mucosal immune response to SARS-CoV-2 and the escape mechanisms employed by the virus, which are unfortunately not well pursued. I recently discovered that SARS-CoV-2 Open Reading Frame (ORF) 8 protein downregulates the polymeric immunoglobulin receptor (pIgR). This receptor is a key mediator of mucosal immunity as it transcytoses dimeric IgA (dIgA) from the blood to the mucosa of airways in the lungs, which is the primary site of SARS-CoV-2 infection. This discovery led to the hypothesis that ORF8 antagonizes dIgA-mediated mucosal immunity by downregulating pIgR, thus promoting SARS-CoV-2 infection of lung epithelial cells. This project aims to elucidate the molecular mechanism of ORF8-mediated pIgR downregulation by investigating the interaction between both proteins via mutagenesis. Furthermore, we seek to determine the effect of ORF8 from SARS-CoV-2 and its variants in the antagonization of dIgA transport by pIgR. This study will advance our knowledge of SARS-CoV-2 immune evasion mechanisms and highlight ORF8 as a potential mucosal vaccine target due to its capacity to antagonize mucosal immunity.