@article{Dixon_C-2024_183955,
title = {Structural epitope profiling identifies antibodies associated with critical COVID-19 and long COVID},
author = {Dixon, C. and Badonyi, M. and Lee, K. and Czapiewski, R. and Fleming, O. and Nadukkandy, P. and Gerasimavicius, L. and Sahputra, R. and Marsh, J. and Gilbert, N. and Kearns, P.},
month = {sep},
year = {2024},
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 (&gt; 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.},
volume = {1},
journal = {eLIFE},
publisher = {eLife Sciences Publications},
url = {https://doi.org/10.7554/eLife.98840.1.sa3},
}
