An article in The Atlantic on the effects of COVID-19 on children included input from McGowan Institute for Regenerative Medicine affiliated faculty member Ivet Bahar, PhD, Distinguished Professor, the John K. Vries Chair, and the Founding Chair in the Department of Computational & Systems Biology at the University of Pittsburgh School of Medicine. Dr. Bahar’s work, which appeared in the PNAS in September 2020, was referenced as a part of the author’s research. Roxanne Khamsi wrote the story for The Atlantic.
Ms. Khamsi reports on the occasionally fatal, COVID-related condition known as multisystem inflammatory syndrome in children (MIS-C). When kids first started showing signs of MIS-C in early 2020—rash or conjunctivitis; low blood pressure; diarrhea or vomiting; etc.—doctors guessed it was an inflammatory disease that occurs most often in toddlers called Kawasaki disease. Now most experts believe it’s a separate condition, affecting kids at an average age of 8. No more than a few hundred children in the U.S. have died from COVID-19 during the pandemic—compared with more than half a million deaths overall—but more than 4,000 have developed MIS-C, and doctors still don’t have foolproof ways to cure it. But a handful of scientists think they’ve found important clues about what drives MIS-C. The disease, they say, may have something to do with a dangerous condition most commonly associated with tampon use.
Dr. Bahar’s lab found a resemblance between the SARS-CoV-2 spike protein, which allows the pandemic virus to infect human cells, and the Staphylococcus superantigen toxin. “This level of similarity, both in sequence and structure with the bacterial toxin, tells us for sure that this segment of spike has the same behavior,” Dr. Bahar told Ms. Khamsi.
The abstract from Dr. Bahar’s PNAS paper entitled, “Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation,” follows:
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 form a 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.
Ms. Khamsi concludes, that for now, the fact that SARS-CoV-2 might function as a superantigen in children (as well as some adults) underscores a risk that may be growing. Youngsters who are not yet immunized against COVID-19 would be the most important beneficiaries of a better understanding of this link.
Abstract (Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation. Mary Hongying Cheng, She Zhang, Rebecca A. Porritt, Magali Noval Rivas, Lisa Paschold, Edith Willscher, Mascha Binder, Moshe Arditi, and Ivet Bahar. PNAS, October 13, 2020, 117 (41) 25254-25262; first published September 28, 2020.)