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.

Grant Number: 5F31AI179125-02
NIH Institute/Center: NIH
Principal Investigator: Leslie Chan