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

View ORCID ProfileMary Hongying Cheng, View ORCID ProfileShe Zhang, View ORCID ProfileRebecca A. Porritt, View ORCID ProfileMoshe Arditi, View ORCID ProfileIvet Bahar
doi: https://doi.org/10.1101/2020.05.21.109272
Mary Hongying Cheng
aDepartment of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261
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She Zhang
aDepartment of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261
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Rebecca A. Porritt
bDepartment of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
cDepartment of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
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Moshe Arditi
bDepartment of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
cDepartment of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
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  • For correspondence: bahar@pitt.edu Moshe.arditi@cshs.org
Ivet Bahar
aDepartment of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261
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  • For correspondence: bahar@pitt.edu Moshe.arditi@cshs.org
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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 α- and β-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.

Significance Although children have been largely spared from severe COVID-19 disease, a rare hyperinflammatory syndrome has been described in Europe and the East Coast of the United States, termed Multisystem Inflammatory Syndrome in Children (MISC). The symptoms and diagnostic lab values of MIS-C resemble those of toxic shock, typically caused by pathogenic superantigens stimulating excessive activation of the adaptive immune system. We show that SARS-CoV-2 spike has a sequence and structure motif highly similar to those of bacterial superantigens, and may directly bind to the T cell receptors. This sequence motif, not present in other coronaviruses, may explain the unique potential for SARS-CoV-2 to cause both MIS-C and the cytokine storm observed in adult COVID-19 patients.

Competing Interest Statement

Patent filing process started for short peptide sequences to neutralize the superantigenic fragment.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 21, 2020.
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An insertion unique to SARS-CoV-2 exhibits superantigenic character strengthened by recent mutations
Mary Hongying Cheng, She Zhang, Rebecca A. Porritt, Moshe Arditi, Ivet Bahar
bioRxiv 2020.05.21.109272; doi: https://doi.org/10.1101/2020.05.21.109272
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An insertion unique to SARS-CoV-2 exhibits superantigenic character strengthened by recent mutations
Mary Hongying Cheng, She Zhang, Rebecca A. Porritt, Moshe Arditi, Ivet Bahar
bioRxiv 2020.05.21.109272; doi: https://doi.org/10.1101/2020.05.21.109272

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