- Published
- 02 September 2024
- Journal article
Structural epitope profiling identifies antibodies associated with critical COVID-19 and long COVID
- Authors
- Source
- eLIFE
Abstract
Even within a single protein, antibody binding can have beneficial, neutral, or harmful effects during the response to infection. Resolving a polyclonal antibody repertoire across a pathogen’s proteome to specific epitopes may therefore explain much of the heterogeneity in susceptibility to infectious disease. However, the three-dimensional nature of antibody-epitope interactions makes the discovery of non-obvious targets challenging. We implemented a novel computational method and synthetic biology pipeline for identifying epitopes that are functionally important in the SARS-CoV-2 proteome and identified an IgM-dominant response to an exposed Membrane protein epitope which to our knowledge is the strongest correlate of severe disease identified to date (adjusted OR 72.14, 95% CI: 9.71 – 1300.15), stronger even than the exponential association of severe disease with age. We also identify persistence (> 2 years) of this IgM response in individuals with longCOVID, and a correlation with fatigue and depression symptom burden. The repetitive arrangement of this epitope and the pattern of isotype class switching is consistent with this being a previously unrecognized T independent antigen. These findings point to a coronavirus host-pathogen interaction characteristic of severe virus driven immune pathology. This epitope is a promising vaccine and therapeutic target as it is highly conserved through SARS-CoV-2 variant evolution in humans to date and in related coronaviruses (e.g. SARS-CoV), showing far less evolutionary plasticity than targets on the Spike protein. This provides a promising biomarker for longCOVID and a target to complement Spike-directed vaccination which could broaden humoral protection from severe or persistent disease or novel coronavirus spillovers.
Rights
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. http://creativecommons.org/licenses/by/4.0/
Cite as
Dixon, C., Badonyi, M., Lee, K., Czapiewski, R., Fleming, O., Nadukkandy, P., Gerasimavicius, L., Sahputra, R., Marsh, J., Gilbert, N. & Kearns, P. 2024, 'Structural epitope profiling identifies antibodies associated with critical COVID-19 and long COVID'. To be published in eLIFE [Preprint], 1. Available at: https://doi.org/10.7554/eLife.98840.1.sa3