Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-10, Vol.117 (41), p.25254-25262
• Main Authors: Cheng, Mary Hongying, Zhang, She, Porritt, Rebecca A., Rivas, Magali Noval, Paschold, Lisa, Willscher, Edith, Binder, Mascha, Arditi, Moshe, Bahar, Ivet
• Format: Article
• Language: English
• Subjects: Adaptive immunity; Amino Acid Motifs; Betacoronavirus - chemistry; Betacoronavirus - genetics; Betacoronavirus - immunology; Betacoronavirus - metabolism; Binding; Biological Sciences; Cell adhesion; Children; Computational neuroscience; Constellations; Coronaviridae; Coronavirus Infections - genetics; Coronavirus Infections - immunology; Coronavirus Infections - pathology; Coronaviruses; COVID-19; Cytokine storm; Cytokines; Cytotoxicity; Enterotoxins - chemistry; Epitopes; Epitopes, T-Lymphocyte; Glycoproteins; Humans; Immune response; Inflammation; Intercellular Adhesion Molecule-1 - chemistry; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Models, Molecular; Molecular structure; Multisystem inflammatory syndrome in children; Mutation; Neurotoxins; Neurotoxins - chemistry; Pandemics; Physical Sciences; Pneumonia, Viral - genetics; Pneumonia, Viral - immunology; Pneumonia, Viral - pathology; Protein Binding; Receptors; Receptors, Antigen, T-Cell - chemistry; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Respiratory diseases; SARS-CoV-2; Septic shock; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Signs and symptoms; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - metabolism; Spikes; Staphylococcal enterotoxin B; Superantigens; Superantigens - chemistry; Superantigens - genetics; Superantigens - metabolism; Systemic Inflammatory Response Syndrome - genetics; Systemic Inflammatory Response Syndrome - immunology; Systemic Inflammatory Response Syndrome - pathology; T cell receptors; Toxic shock syndrome; Toxins; Viral diseases; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2010722117

Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 is a newly recognized condition in children with recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These children and adult patients with severe hyperinflammation present with a constellation of symptoms that strongly resemble toxic shock syndrome, an escalation of the cytotoxic adaptive immune response triggered upon the binding of pathogenic superantigens to T cell receptors (TCRs) and/or major histocompatibility complex class II (MHCII) molecules. Here, using structure-based computational models, we demonstrate that the SARS-CoV-2 spike (S) glycoprotein exhibits a high-affinity motif for binding TCRs, and may forma ternary complex with MHCII. The binding epitope on S harbors a sequence motif unique to SARS-CoV-2 (not present in other SARS-related coronaviruses), which is highly similar in both sequence and structure to the bacterial superantigen staphylococcal enterotoxin B. This interaction between the virus and human T cells could be strengthened by a rare mutation (D839Y/N/E) from a European strain of SARS-CoV-2. Furthermore, the interfacial region includes selected residues from an intercellular adhesion molecule (ICAM)-like motif shared between the SARS viruses from the 2003 and 2019 pandemics. A neurotoxin-like sequence motif on the receptor-binding domain also exhibits a high tendency to bind TCRs. Analysis of the TCR repertoire in adult COVID-19 patients demonstrates that those with severe hyperinflammatory disease exhibit TCR skewing consistent with superantigen activation. These data suggest that SARS-CoV-2 S may act as a superantigen to trigger the development of MIS-C as well as cytokine storm in adult COVID-19 patients, with important implications for the development of therapeutic approaches.