Haley Aull - Graduate Student, Immunology, Microbiology, and Virology Ph.D. Program
BST2/Tetherin is an antiviral factor that broadly restricts enveloped viruses. BST2 tethers nascent virions to the cell surface by embedding itself into cellular and viral membranes. Tethering not only limits viral release, it also facilitates adaptive immune recognition of the infecting virus. Tethered virions are opsonized by antibodies, which can be recognized by Fc receptors on both natural killer cells and macrophages, activating said effector to phagocytose or kill the infected target cell.
Previously, we have identified that SARS-CoV-2 is susceptible to BST2 restriction. However, the virus has evolved to use its Spike to downregulate BST2. Downregulation is achieved by an interaction between Spike and the extracellular domains of BST2, routing BST2 for lysosomal degradation in a Clathrin- and Ubiquitin-dependent manner. Additionally, we found that later variants of concern have enhanced abilities to downregulate BST2, such that they completely escape BST2’s restriction. Here, we asked (1) the mechanism by which Spike routes BST2 for lysosomal degradation, and (2) what implications BST2 antagonism has on antibody-mediated cellular responses. First, I have identified that BST2 is ubiquitinated in the presence of Spike, and this ubiquitination is required for its downregulation. Next, I have identified that the clathrin adaptor AP1 is required for Spike mediated downregulation of BST2. Finally, to test whether BST2 antagonism relieves pressure from antibody-mediated cellular responses such as ADCC and ADCP, I have adapted reporter virus-based systems to measure infected cell killing and phagocytosis. Using this assay, I have demonstrated that BST2 enhances both ADCC and ADCP killing of SARS-CoV-2 infected cells.
Dec 05, 2024 @ 12:00 p.m.
Medical Center | K307 (3-6408)
Host: Advisor: Ruth Serra-Moreno, PhD