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Mannar, Dhiraj

University of British Columbia

The COVID-19 pandemic erupted in 2019 and went on to have devastating impacts on global health and economies. The causative agent of COVID-19 is a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was found to cause respiratory illness in humans, with symptoms ranging from mild to life threatening (pneumonia, multi-system organ failure). Like previous disease-causing coronaviruses, SARS-CoV-2 relies on a spike glycoprotein to recognize and infect human cells; and antibodies that target the spike protein can prevent viral entry from occurring, effectively neutralizing the virus. However, viruses possess the ability to evolve, and previous experience with other coronaviruses has set the precedence for spike proteins evolving altered antigenic properties and epitopes, permitting escape from neutralizing antibodies. This thesis represents efforts to respond to the COVID-19 pandemic in real time, as we sought to first define the antigenic properties and vulnerabilities of the SARS-CoV-2 spike protein, and then proceed to characterize emerging spike protein mutations and variants, with an emphasis on spike protein structure, receptor binding, and antibody neutralization. We identified antigenic and vulnerable regions in the spike protein amino terminal domain and receptor binding domain and describe heterogenous ways in which antibodies can bind epitopes within these regions. Over the course of the pandemic, significant mutational drift was observed within these regions. We found that mutations within the receptor binding domain were modular in nature, and when combined to represent variant strains of SARS-CoV-2, served to simultaneously prevent recognition of neutralizing antibodies, and enhance or preserve receptor binding affinity. Analysis of variant spike proteins showed that there was high architectural conservation across most variants, with one glaring exception revealing a novel dimers-of-trimers assembly. All variant spike proteins were antibody evasive, with some exhibiting concerning escape from immunized and convalescent sera. Structural analyses on the amino terminal and receptor binding domains of these variants revealed mutational mechanisms underpinning antigenic drift and rationalizing antibody escape. Finally, we structurally defined an epitope on the spike protein that enables broad neutralization of several variants, offering hope for the development of broadly effective therapies to combat variants of SARS-CoV-2.

Text

2023-07-04

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/85188

Biochemistry and Molecular Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/