Molecular mimicry between viral antigens and host proteins can produce cross-reacting antibodies leading to autoimmunity. The coronavirus SARS-CoV-2 causes COVID-19, a disease curiously resulting in varied symptoms and outcomes, ranging from asymptomatic to fatal. Autoimmunity due to cross-reacting antibodies resulting from molecular mimicry between viral antigens and host proteins may provide an explanation. Thus, we computationally investigated molecular mimicry between SARS-CoV-2 Spike and known epitopes. We discovered molecular mimicry hotspots in Spike and highlight two examples with tentative high autoimmune potential and implications for understanding COVID-19 complications. We show that a TQLPP motif in Spike and thrombopoietin shares similar antibody binding properties. Antibodies cross-reacting with thrombopoietin may induce thrombocytopenia, a condition observed in COVID-19 patients. Another motif, ELDKY, is shared in multiple human proteins, such as PRKG1 involved in platelet activation and calcium regulation, and tropomyosin, which is linked to cardiac disease. Antibodies cross-reacting with PRKG1 and tropomyosin may cause known COVID-19 complications such as blood-clotting disorders and cardiac disease, respectively. Our findings illuminate COVID-19 pathogenesis and highlight the importance of considering autoimmune potential when developing therapeutic interventions to reduce adverse reactions.

Most viruses have small genomes that encode proteins needed to perform essential enzymatic functions. Across virus families, primary enzyme functions are under functional constraint; however, secondary functions mediated by exposed protein surfaces that promote interactions with the host proteins may be less constrained. Viruses often form transient interactions with host proteins through conformationally flexible interfaces. Exposed flexible amino acid residues are known to evolve rapidly suggesting that secondary functions may generate diverse interaction potentials between viruses within the same viral family. One mechanism of interaction is viral mimicry through short linear motifs (SLiMs) that act as functional signatures in host proteins. Viral SLiMs display specific patterns of adjacent amino acids that resemble their host SLiMs and may occur by chance numerous times in viral proteins due to mutational and selective processes. Through mimicry of SLiMs in the host cell proteome, viruses can interfere with the protein interaction network of the host and utilize the host-cell machinery to their benefit. The overlap between rapidly evolving protein regions and the location of functionally critical SLiMs suggest that these motifs and their functional potential may be rapidly rewired causing variation in pathogenicity, infectivity, and virulence of related viruses. The following review provides an overview of known viral SLiMs with select examples of their role in the life cycle of a virus, and a discussion of the structural properties of experimentally validated SLiMs highlighting that a large portion of known viral SLiMs are devoid of predicted intrinsic disorder based on the viral SLiMs from the ELM database.

Thrombocytopenia, characterized by reduced platelet count, increases mortality in COVID-19 patients. We performed a computational investigation of antibody-induced cross-reactivity due to molecular mimicry between SARS-CoV-2 Spike protein and human thrombopoietin, the regulator of platelet production, as a mechanism for thrombocytopenia in COVID-19 infections. The presence of a common sequence motif with similar structure and antibody-binding properties for these proteins strongly indicate shared molecular mimicry. Recent reports of antibodies in COVID-19 patients and pre-pandemic samples against epitopes containing the motif offer additional support for the cross-reactivity. Altogether, this suggests cross-reactivity between an antibody with affinity for Spike protein and a human protein. Consideration of cross-reactivity for SARS-CoV-2 is important for therapeutic intervention and when designing the next generation of COVID-19 vaccines to avoid potential autoimmune interference.

Motivation: Upon infection, pathogen epitopes stimulate the host immune system to produce antibodies targeting the pathogen. Molecular mimicry (structural similarity) between an infecting pathogen and host proteins or pathogenic proteins the host has previously encountered can impact the immune response of the host. The ability to identify potential molecular mimicry for a pathogen can illuminate immune effects with importance to pathogen treatment and vaccine design. Summary: Epitopedia allows for identification of regions with three-dimensional molecular mimicry between a protein in a pathogen with known epitopes in the host. Results: SARS-CoV-2 Spike returns molecular mimicry with 14 different epitopes including integrin beta-1 from Homo sapiens, lethal factor precursor from Bacillus anthracis, and pollen allergen Phl p 2 from Timothy grass. Availability: Epitopedia is primarily written in Python and relies on established software and databases. Epitopedia is available at https://github.com/cbalbin-FIU/Epitopedia under the opensource MIT license and is also packaged as a docker container at https://hub.docker.com/r/cbalbin/epitopedia.

Epitope-based molecular mimicry occurs when an antibody cross-reacts with two different antigens due to structural and chemical similarities. Molecular mimicry between proteins from two viruses can lead to beneficial cross-protection when the antibodies produced by exposure to one also react with the other. On the other hand, mimicry between a protein from a pathogen and a human protein can lead to auto-immune disorders if the antibodies resulting from exposure to the virus end up interacting with host proteins. While cross-protection can suggest the possible reuse of vaccines developed for other pathogens, cross-reaction with host proteins may explain side effects. There are no computational tools available to date for a large-scale search of antibody cross-reactivity. We present a comprehensive Epitope-based Molecular Mimicry Search (EMoMiS) pipeline for computational molecular mimicry searches. EMoMiS, when applied to the SARS-CoV-2 Spike protein, identified eight examples of molecular mimicry with viral and human proteins. These findings provide possible explanations for (a) differential severity of COVID-19 caused by cross-protection due to prior vaccinations and/or exposure to other viruses, and (b) commonly seen COVID-19 side effects such as thrombocytopenia and thrombophilia. Our findings are supported by previously reported research but need validation with laboratory experiments. The developed pipeline is generic and can be applied to find mimicry for novel pathogens. It has applications in improving vaccine design. The developed Epitope-based Molecular Mimicry Search Pipeline (EMoMiS) is available from https://biorg.cs.fiu.edu/emomis/.