Genetic alteration of human MYH6 is mimicked by SARS-CoV-2 polyprotein

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Acute cardiac injury has been observed in a subset of COVID-19 patients, but the molecular basis for this clinical phenotype is unknown.

It has been hypothesized that molecular mimicry may play a role in triggering an autoimmune inflammatory reaction in some individuals after SARS-CoV-2 infection. 

Furthermore, analysis of 4.85 million SARS-CoV-2 genomes from over 200 countries shows that viral evolution has already resulted in 20 additional 8-mer peptides that are identical to human heart-enriched proteins encoded by reference sequences or genetic variants.

Whether such mimicry contributes to cardiac inflammation during or after COVID-19 illness warrants further experimental evaluation. 

The study findings were published on a preprint server and are currently being peer reviewed. 

https://www.biorxiv.org/content/10.1101/2021.11.23.469709v1

Cardiac injury is a prevalent complication associated with COVID-19.1 In a study of 100 recently recovered COVID-19 patients, cardiovascular magnetic resonance imaging revealed cardiac involvement or ongoing myocardial inflammation in 78 and 60 patients, respectively.2

In another study of 39 consecutive autopsies from patients who died of COVID-19, viral RNA was detectable in the heart of 24 (62%) patients.

A large nationwide study from Israel reported that SARS-CoV-2 infection is associated with increased rates of myocarditis, arrhythmia, myocardial infarction, and pericarditis.3

Myocarditis has also been reported in a small fraction of individuals after receiving an mRNA COVID-19 vaccine.4–6

Despite these phenotypic associations, the mechanisms underlying myocardial inflammation in the setting of COVID-19 infection and vaccination remain unclear. A prevalent hypothesis, known as molecular mimicry, posits that T lymphocytes and/or antibodies that recognize SARS-CoV-2 antigens and mediate virus neutralization may also cross-react against host cardiac proteins and trigger an autoimmune response against cardiomyocytes.7

This mechanism has also been suggested to contribute to other inflammatory conditions seen in the context of COVID-19 infection.8–10 Indeed, autoimmune sequelae of other infectious diseases have been attributed to mimicry between host and microbial antigens.11–16

Advances in next-generation sequencing technologies have facilitated the rapid development of large-scale multi-omic datasets and genomic epidemiology resources to better understand the COVID-19 pandemic. Bulk and single cell RNA-sequencing datasets have elucidated the transcriptional signatures of most healthy human tissues and cell types.17–20

Amino acid sequences of human proteins, including genetic variants and immunologic epitopes, are available in UniProt21, gnomAD22, and Immune Epitope Database (IEDB)23. The GISAID database currently hosts 4.85 million SARS-CoV-2 genomes from more than 200 countries.24 The availability of such genome-scale data enables us to investigate the potential for molecular mimicry between SARS-CoV-2 and human cardiac proteins.

Here we present a systematic comparison of peptides from human cardiac proteins and SARS-CoV-2 proteins. We show that no 8-mer peptides are identical between the reference sequences of these two groups of proteins. However, when including human and viral genetic variants in this comparison, we found 21 8-mer peptides to be identical between human cardiac proteins and SARS-CoV-2 proteins.

Among these, a human genetic variant of MYH6 (c.5410C>A; Q1804K) is identical to a peptide of the reference SARS-CoV-2 replicase polyprotein. Finally, we propose that the SARS-CoV-2 variants that have peptides identical to human cardiac proteins should be studied as potential ‘viral variants of cardiac interest’.

Figure 1.
Figure 1.Identification of mimicked peptides between SARS-CoV-2 and human proteinsa. Identification of cardiac specific proteins based on analysis of bulk RNAseq and single-cell RNAseq data and identification of SARS-CoV-2 proteins. b. Comparison of peptide libraries of human cardiac proteins and SARS-CoV-2 proteins.

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