Breaking! Sars-Cov-2 Replicase Polyprotein 1a/1ab (Kialkggk) Could Be Mimicking Human Cardiac Protein MYH6 Resulting In Cardiac Injury!
: A new study by researchers from nference Labs-Bengaluru-India, nference Labs-Cambridge-USA and Southcoast Health-Massachusetts has found that Sars-Cov-2 replicase polyprotein 1a/1ab (Kialkggk) could be mimicking human cardiac protein MYH6 and causing cardiac injury. Both are 8-mer peptides.
It has been noted that 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.
The study team investigated if linear peptides contained in proteins that are primarily expressed in the heart also occur in the SARS-CoV-2 proteome.
Specifically, the study team compared the library of 136,704 8-mer peptides from 144 human proteins (including splicing variants) to 9,926 8-mers from all 17 viral proteins in the reference SARS-CoV-2 proteome.
The study findings showed that no 8-mers were exactly identical between the reference human proteome and the reference SARS-CoV-2 proteome.
However, there were 45 8-mers that differed by only one amino acid when compared to the reference SARS-CoV-2 proteome.
Importantly, analysis of protein-coding mutations from 141,456 individuals showed that one of these 8-mers from the SARS-CoV-2 Replicase polyprotein 1a/1ab (KIALKGGK) is identical to a MYH6
peptide encoded by the c.5410C>A (Q1804K) genetic variation, which has been observed at low prevalence in Africans/African Americans (0.08%), East Asians (0.3%), South Asians (0.06%) and Latino/Admixed Americans (0.003%).
Detailed 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 suggest that SARS-CoV-2 variants harboring peptides identical to human cardiac proteins should be investigated as ‘viral variants of cardiac interest’.
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
To date, cardiac injury is a prevalent complication associated with COVID-19. However, the molecular basis for this phenotype is not clear.
studies have documented the prevalence of cardiac injury associated with COVID-19. In a small number of cases, myocarditis has been reported after receiving an mRNA COVID-19 vaccine. However, the mechanisms underlying myocardial inflammation during COVID-19 infection and vaccination remain unknown.
The possibility of molecular mimicry is one hypothesis that states that T lymphocytes and/or antibodies recognizing SARS-CoV-2 antigens and mediating virus neutralization may react with host cardiac proteins and trigger
an autoimmune response against cardiomyocytes.
Fortunately advances in sequencing technologies have aided the development of large-scale multi-omic datasets and genomic epidemiology resources. These new resources have elucidated the transcriptional signatures of many healthy human tissues and cell types. Over 200 countries have contributed more than 4.85 million SARS-CoV-2 genomes to the GISAID database. Such large-scale datasets have enabled researchers to study the potential for molecular mimicry between human cardiac proteins and SARS-CoV-2.
The SARS-CoV-2 Research
team compared the library of 136,704 8-mer peptides from 144 human proteins to 9,926 8-mers from all 17 viral proteins in the reference SARS-CoV-2 proteome. The human proteins included splicing variants as well.
Detailed analysis revealed that no 8-mers were identical between the SARS-CoV-2 proteome and the human reference proteome. It was, however, interesting to note that 45 8-mers differed by only one amino acid.
Importantly protein-coding mutations from 141,456 individuals were analyzed, and the results obtained showed that one of these 8-mers from the SARS-CoV-2 Replicase polyprotein 1a/1ab (KIALKGGK) was exactly identical to an MYH6 peptide encoded by the c.5410C>A (Q1804K) genetic variation.
Interestingly this genetic variation has low prevalence in many sub-groups. For example, 0.08% of Africans/African Americans, 0.3% of East Asians, 0.06% of South Asians, and 0.003% of Latino/Admixed Americans show this genetic variation.
The study team further analyzed 4.85 million SARS-CoV-2 genomes from over 200 countries and showed that viral evolution has resulted in 20 additional 8-mer peptides. These peptides are identical to human heart-enriched proteins encoded by reference sequences or genetic variants.
Future research will need to reveal if such mimicry causes cardiac inflammation during or after COVID-19 illness.
The study team recommended a deeper investigation of SARS-CoV-2 variants that harbor peptides identical to human cardiac proteins as ‘viral variants of cardiac interest’.
Importantly, the potential for molecular mimicry between the antigen encoded by mRNA vaccines and human cardiac proteins should also be studied, given the occurrence of myocarditis in some individuals shortly after receiving an mRNA-based COVID-19 vaccine.
The surveyed human proteins were selected based on their overexpression in cardiac tissue. Mimicked proteins may be shared between cardiac tissues and other tissues, and these were not accounted for in the current analysis.
Other mechanisms (e.g., bystander activation, epitope spreading, and viral persistence) could lead to autoimmunity affecting the cardiac tissues after viral infection.
Also, it could be a matter of pure chance that identical peptides are present in cardiac proteins and the SARS-CoV-2 proteome.
It could also well be the case that peptides with lesser degrees of similarity could contribute to immunologic mimicry.
Detailed analysis of the overlap between human genetic variation in cardiac proteins and SARS-CoV-2 evolution made it possible for the study team to identify prospective molecular mimicry candidates.
Alarmingly these candidates possess the potential to contribute to cardiac inflammation during COVID-19 disease.
Follow-up functional studies to determine the potential of SARS-CoV-2 reactive T cells and antibodies to cross-react with these peptides will be necessary and crucial.
The study team also highlighted that this strategy could be generalized to identify and categorize possible mimicry candidates from a wide variety of human tissues affected by other autoimmune responses in individuals with COVID-19.
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