The emergence of the novel SARS-CoV-2 virus is the most important public-health issue of our time. Understanding the diverse clinical presentations of the ensuing disease, COVID-19, remains a critical unmet need. Here we present a comprehensive listing of the diverse clinical indications associated with COVID-19. We explore the theory that anti-SARS-CoV-2 antibodies could cross-react with endogenous human proteins driving some of the pathologies associated with COVID-19. We describe a novel computational approach to estimate structural homology between SARS-CoV-2 proteins and human proteins. Antibodies are more likely to interrogate 3D-structural epitopes than continuous linear epitopes. This computational workflow identified 346 human proteins containing a domain with high structural homology to a SARS-CoV-2 Wuhan strain protein. Of these, 102 proteins exhibit functions that could contribute to COVID-19 clinical pathologies. We present a testable hypothesis to delineate unexplained clinical observations vis-à-vis COVID-19 and a tool to evaluate the safety-risk profile of potential COVID-19 therapies.
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