Mechanisms of Antibody-Mediated Immunity Against Class 1 Viral Fusion Glycoproteins

Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology

First Advisor

Mothes, Walther

Abstract

Class 1 fusion glycoproteins (spikes) decorate the outside of enveloped viruses and mediate virus entry into host cells through driving fusion of the virus and host cell membranes. Given that these spikes are the most prominent antigen on the surface of viruses, they are a primary target of the humoral immune response and the basis for many vaccines. However, the mechanisms by which antibodies bind, block entry, and elicit immune functions within the native membrane environment remain poorly understood. Towards this end, we have developed system to explore viral spike-host receptor interactions at membrane interfaces to investigate antibody function. We captured spike-entry receptor complexes and downstream fusion events in membranes and discovered how antibodies target a vulnerable, conserved epitope during fusion to neutralize infectivity. We additionally determine structures of antibodies mediating the formation of spike-IgG-FcɣR complexes in membranes and find structural determinants of antibody Fc-mediated immunity. Our results demonstrate how capturing viral spike-host receptor complexes in membranes can reveal sites of vulnerability targeted through distinct humoral immune mechanisms.

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