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An insertion unique to SARS-CoV-2 exhibits superantigenic character strengthened by recent mutations.

ABSTRACT: Multisystem Inflammatory Syndrome in Children (MIS-C) associated with Coronavirus Disease 2019 (COVID-19) is a newly recognized condition in which children with recent SARS-CoV-2 infection present with a constellation of symptoms including hypotension, multiorgan involvement, and elevated inflammatory markers. These symptoms and the associated laboratory values strongly resemble toxic shock syndrome, an escalation of the cytotoxic adaptive immune response triggered upon the binding of pathogenic superantigens to MHCII molecules and T cell receptors (TCRs). Here, we used structure-based computational models to demonstrate that the SARS-CoV-2 spike (S) exhibits a high-affinity motif for binding TCR, interacting closely with both the ?- and ?-chains variable domains' complementarity-determining regions. The binding epitope on S harbors a sequence motif unique to SARS-CoV-2 (not present in any other SARS coronavirus), which is highly similar in both sequence and structure to bacterial superantigens. Further examination revealed that this interaction between the virus and human T cells is strengthened in the context of a recently reported rare mutation (D839Y/N/E) from a European strain of SARS-CoV-2. Furthermore, the interfacial region includes selected residues from a motif shared between the SARS viruses from the 2003 and 2019 pandemics, which has intracellular adhesion molecule (ICAM)-like character. These data suggest that the SARS-CoV-2 S may act as a superantigen to drive the development of MIS-C as well as cytokine storm in adult COVID-19 patients, with important implications for the development of therapeutic approaches.

SUBMITTER: Cheng MH

PROVIDER: S-EPMC7263503 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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An insertion unique to SARS-CoV-2 exhibits superantigenic character strengthened by recent mutations.

Cheng Mary Hongying MH Zhang She S Porritt Rebecca A RA Arditi Moshe M Bahar Ivet I

bioRxiv : the preprint server for biology 20200521

Multisystem Inflammatory Syndrome in Children (MIS-C) associated with Coronavirus Disease 2019 (COVID-19) is a newly recognized condition in which children with recent SARS-CoV-2 infection present with a constellation of symptoms including hypotension, multiorgan involvement, and elevated inflammatory markers. These symptoms and the associated laboratory values strongly resemble toxic shock syndrome, an escalation of the cytotoxic adaptive immune response triggered upon the binding of pathogenic ...[more]

PMID: 32511374

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Project description:The evolutional process of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) development remains inconclusive. This study compared the genome sequences of severe acute respiratory syndrome coronavirus (SARS-CoV), bat coronavirus RaTG13, and SARS-CoV-2. In total, the genomes of SARS-CoV-2 and RaTG13 were 77.9% and 77.7% identical to the genome of SARS-CoV, respectively. A total of 3.6% (1,068 bases) of the SARS-CoV-2 genome was derived from insertion and/or deletion (indel) mutations, and 18.6% (5,548 bases) was from point mutations from the genome of SARS-CoV. At least 35 indel sites were confirmed in the genome of SARS-CoV-2, in which 17 were with ≥10 consecutive bases long. Ten of these relatively long indels were located in the spike (S) gene, five in nonstructural protein 3 (Nsp3) gene of open reading frame (ORF) 1a, and one in ORF8 and noncoding region. Seventeen (48.6%) of the 35 indels were based on insertion-and-deletion mutations with exchanged gene sequences of 7-325 consecutive bases. Almost the complete ORF8 gene was replaced by a single 325 consecutive base-long indel. The distribution of these indels was roughly in accordance with the distribution of the rate of point mutation rate around the indels. The genome sequence of SARS-CoV-2 was 96.0% identical to that of RaTG13. There was no long insertion-and-deletion mutation between the genomes of RaTG13 and SARS-CoV-2. The findings of the uneven distribution of multiple indels and the presence of multiple long insertion-and-deletion mutations with exchanged consecutive base sequences in the viral genome may provide insights into SARS-CoV-2 development. IMPORTANCE The developmental mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains inconclusive. This study compared the base sequence one-by-one between severe acute respiratory syndrome coronavirus (SARS-CoV) or bat coronavirus RaTG13 and SARS-CoV-2. The genomes of SARS-CoV-2 and RaTG13 were 77.9% and 77.7% identical to the genome of SARS-CoV, respectively. Seventeen of the 35 sites with insertion and/or deletion mutations between SARS-CoV-2 and SARS-CoV were based on insertion-and-deletion mutations with the replacement of 7-325 consecutive bases. Most of these long insertion-and-deletion sites were concentrated in the nonstructural protein 3 (Nsp3) gene of open reading frame (ORF) 1a, S1 domain of the spike protein, and ORF8 genes. Such long insertion-and-deletion mutations were not observed between the genomes of RaTG13 and SARS-CoV-2. The presence of multiple long insertion-and-deletion mutations in the genome of SARS-CoV-2 and their uneven distributions may provide further insights into the development of the virus.

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An insertion unique to SARS-CoV-2 exhibits superantigenic character strengthened by recent mutations.

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An insertion unique to SARS-CoV-2 exhibits superantigenic character strengthened by recent mutations.

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