Molecular Mimicry Map (3M) of SARS-CoV-2: Prediction of potentially immunopathogenic SARS-CoV-2 epitopes via a novel immunoinformatic approach

Abstract

Currently, more than 33 million peoples have been infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and more than a million people died from coronavirus disease 2019 (COVID-19), a disease caused by the virus. There have been multiple reports of autoimmune and inflammatory diseases following SARS-CoV-2 infections. There are several suggested mechanisms involved in the development of autoimmune diseases, including cross-reactivity (molecular mimicry). A typical workflow for discovering cross-reactive epitopes (mimotopes) starts with a sequence similarity search between protein sequences of human and a pathogen. However, sequence similarity information alone is not enough to predict cross-reactivity between proteins since proteins can share highly similar conformational epitopes whose amino acid residues are situated far apart in the linear protein sequences. Therefore, we used a hidden Markov model-based tool to identify distant viral homologs of human proteins. Also, we utilized experimentally determined and modeled protein structures of SARS-CoV-2 and human proteins to find homologous protein structures between them. Next, we predicted binding affinity (IC50) of potentially cross-reactive T-cell epitopes to 34 MHC allelic variants that have been associated with autoimmune diseases using multiple prediction algorithms. Overall, from 8,138 SARS-CoV-2 genomes, we identified 3,238 potentially cross-reactive B-cell epitopes covering six human proteins and 1,224 potentially cross-reactive T-cell epitopes covering 285 human proteins. To visualize the predicted cross-reactive T-cell and B-cell epitopes, we developed a web-based application “Molecular Mimicry Map (3M) of SARS-CoV-2” (available at https://ahs2202.github.io/3M/). The web application enables researchers to explore potential cross-reactive SARS-CoV-2 epitopes alongside custom peptide vaccines, allowing researchers to identify potentially suboptimal peptide vaccine candidates or less ideal part of a whole virus vaccine to design a safer vaccine for people with genetic and environmental predispositions to autoimmune diseases. Together, the computational resources and the interactive web application provide a foundation for the investigation of molecular mimicry in the pathogenesis of autoimmune disease following COVID-19.

Shared 6mer Peptides of Human and Omicron (21K and 21L) at SARS-CoV-2 Mutation Sites

“…Molecular mimicry is a possible mechanism of autoimmunity induction after infection and even vaccination, where Kanduc and Shoenfeld [ 26 , 27 , 28 ], and several authors have studied that possibility, along with disease severity upon infection [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. A molecular mimicry map of SARS-CoV-2 was also generated [ 38 ], and earlier [ 39 ], autoimmune-linked MHC alleles (class I and class II) were published [ 38 , 40 , 41 , 42 , 43 , 44 ]. Emerging variants of concern, specifically the widespread Omicron variant, drew attention [ 45 , 46 , 47 ] without an Omicron-sourced autoimmunity focus, despite some literature with a broader or a different focus [ 48 , 49 , 50 ].…”

SARS-CoV-2 mass vaccination: Urgent questions on vaccine safety that demand answers from international health agencies, regulatory authorities, governments and vaccine developers

“…Despite this evidence and the extremely limited data on safety and efficacy of SARS-CoV-2 vaccines in the elderly, mass-vaccination campaigns have focused on this age group from the start. Most trials also excluded pregnant and lactating volunteers, as well as those with chronic and serious conditions such as tuberculosis, hepatitis C, autoimmunity, coagulopathies, cancer, and immune suppression [16][17][18][19][20][21][22][23][24][25][26][27][28][29], although these recipients are now being offered the vaccine under the premise of safety.…”

“…SARS-CoV-2 has numerous immunogenic proteins, and all but one of its immunogenic epitopes have similarities to human proteins [27]. These may act as a source of antigens, leading to autoimmunity [28]. While it is true that the same effects could be observed during natural infection with SARS-CoV-2, vaccination is intended for most of the world population, while it is estimated that only 10% of the world population has been infected by SARS-CoV-2, according to Dr. Michael Ryan, head of emergencies at the World Health Organization.…”

Predicted structural mimicry of spike receptor-binding motifs from highly pathogenic human coronaviruses

“…Detecting similar microbial proteins may reveal shared host receptors or antibody cross-immunity (Huang et al, 2020). Short linear motifs on coronavirus spike RBMs have been shown to share high amino acid sequence identity with human proteins, which may indicate host mimicry (An and Park, 2020;Grifoni et al, 2020;Lin et al, 2020;Lucchese and Flöel, 2020). However, protein structure and fold similarity have been shown as more informative than amino acid sequence similarity in predicting molecular mimicry (Krishna and Grishin, 2004;Westall, 2006).…”