Consistent with a hypothesis that the mechanism driving the non-switching response was T independent B cell activation, we find that B cells secrete IgM and proliferate on exposure to virus-like particles lacking Spike. We show patterns of epitope-binding antibodies associated with immunopathology, including a non-isotype switching IgM response to a Membrane protein epitope which is amongst the strongest immunological features associated with severe COVID-19 to date (adjusted OR 72.14, 95% CI: 9.71 – 1300.15). ![]() We describe and experimentally validated a novel computational method and synthetic biology pipeline for identifying epitopes that are structurally stable and functionally important and apply it to the SARS-CoV-2 proteome. ![]() However, the three-dimensional nature of antibody-epitope interactions limits discovery of important targets. ![]() Antibodies can have beneficial, neutral, or harmful effects so resolving an antibody repertoire to its target epitopes may explain heterogeneity in susceptibility to infectious disease.
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