Defining factors affecting natural killer cells' antibody-dependent responses in COVID-19

PROJECT SUMMARY SARS-CoV-2, the causative agent of COVID-19, has become an extended public health challenge due to the emergence of variants that results in reduced protection by vaccination and prior infection. As innate immune cells that recognize and lyse infected or stressed cells, natural killer (NK) cells are uniquely poised to respond to SARS-CoV-2 variants capable of escaping antigen-specific immune responses. NK cells can potently target virus-infected cells via antibody-dependent responses even if the host antibodies have poor neutralizing activity. While the ability of NK cells to mediate antibody-dependent responses could significantly influence disease pathogenesis, the factors affecting NK cells' antibody-dependent responses are understudied. My proposed research seeks to resolve these critical gaps in our knowledge of the immune response to SARS-CoV-2. I hypothesize that SARS-CoV-2 infection, immunosuppressant treatment, and acquisition of surface molecules from infected cells impair the antibody-dependent responses of NK cells. To test this hypothesis, I will 1) identify how COVID-19 vaccination and infection influence the ability of memory-like NK cells to perform antibody-dependent responses; 2) elucidate how immunosuppressant drugs interact with COVID-19 cytokines to affect NK cells' antibody-dependent responses; and 3) define mechanisms by which trogocytosis, the acquisition of surface molecules, from SARS-CoV-2-infected cells impairs NK cells' antibody-dependent responses. In Aim 1, I will compare NK cells' antibody-dependent responses across different COVID-19 patient groups and build upon my training in immune cells' surface proteomics analysis to evaluate intracellular signaling activity. In Aim 2, I will co-culture NK cells with SARS-CoV-2-infected cells to elucidate the impact of immunosuppressant drugs on NK cells' antibody-dependent response. In Aim 3, I will gain training in dissecting NK cells' ligand interactions and NK cell engineering to define mechanisms by which trogocytosis can impair NK cells' functions. My BSL3 certification and training to work with SARS-CoV-2, combined with my experiences in evaluating NK cells' functions, uniquely qualify me to carry out this proposed research. This research plan will provide me with robust training in assessing NK cell responses to virus-infected cells through the establishment of co-culture systems. Notably, my proposed research on trogocytosis is a particularly novel research area and gives me the opportunity to creatively pursue an understudied topic of interest by identifying the tools appropriate for this research. This work will be the first to determine the mechanisms by which NK cells' antibody-dependent responses are regulated in infection, with therapeutic implications for COVID-19 and other infectious diseases.