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Developmental Biology - SARS-CoV-2 Spike Inflammation

COVID19 "Cytokine Storms"

Computer model shows how COVID-19 could ignite runaway inflammation...


A study from the University of Pittsburgh School of Medicine and Cedars-Sinai addresses a mystery 1st raised in March: Why do some people with COVID-19 develop severe inflammation? Research now shows the molecular structure and sequence of SARS-CoV-2 spike proteins extending from the COVID-19 virus, could be causing the inflammatory syndrome in patients.

The study, published in the Proceedings of the National Academy of Sciences or PNAS, uses computer modeling to zero in on this part of the SARS-CoV-2 spike protein which may act as a "superantigen," kicking our immune system into overdrive - a toxic shock syndrome - the rare, life-threatening complication of bacterial infection.
Symptoms of a newly identified condition in pediatric COVID-19 patients, known as Multisystem Inflammatory Syndrome in Children (MIS-C), includes persistent fever and severe inflammation affecting a host of bodily systems. While rare, the syndrome can be serious or fatal.

The first reports of this condition from Europe caught the attention of co-senior author Moshe Arditi MD, director of the Pediatric Infectious Diseases and Immunology Division, Cedars-Sinai Hospital, an expert on Kawasaki disease, a pediatric inflammatory complication.

Arditi contacted his long-time collaborator, Ivet Bahar PhD, distinguished professor and John K. Vries Chair of computational and systems biology at Pitt School of Medicine. The two started searching for features of the SARS-CoV-2 virus that might be responsible for MIS-C. Bahar and her team created a computer model of the interaction between the SARS-CoV-2 viral spike protein and its receptors on human T cells, foot soldiers to our immune system. Under normal circumstances, T cells help our body fight off infection. But when activated in abnormally large quantities, as happens with superantigens, they produce massive amounts of inflammatory cytokines. These small proteins signal the immune system to begin what's known as a "cytokine storm."
The team used their computer model to identify that a specific region on the spike protein has superantigenic features when interacting with T cells. The region compares to a bacterial protein which causes toxic shock syndrome, with striking similarities in both sequence and structure. This proposed SARS-CoV-2 superantigen showed a high affinity for binding T cell receptors a first step towards a runaway immune response.

"Everything came one after another, each time as a huge surprise. The puzzle pieces ended up fitting extremely well," said Bahar, co-senior author.
By finding protein-level similarities between SARS-CoV-2 and the bacterial structure that causes toxic shock syndrome, researchers may have opened up new avenues for treating not only MIS-C patients, but COVID-19 adults experiencing cytokine storms.

Researchers also collaborated with scientists studying adult COVID-19 patients in Germany to find those experiencing severe symptoms had a T cell response similar to people exposed to superantigens and very different from T cell responses in patients with only mild symptoms.
"Our research finally begins to unravel the potential mechanisms involved, raising the possibility therapeutic options for toxic shock syndrome, such as intravenous immunoglobulin and steroids, may be effective for managing and treating MIS-C in children and hyperinflammation in adult coronavirus patients."

Moshe Arditi PhD, Professor, Pediatrics and Biomedical Sciences, Cedars-Sinai.

Arditi's and Bahar's labs are now using these ideas to search for and test antibodies specific to the SARS-CoV-2 superantigen. Their goal is to develop therapies that specifically address MIS-C and cytokine storms in COVID-19 patients.

Significance
A hyperinflammatory syndrome reminiscent of toxic shock syndrome (TSS) is observed in severe COVID-19 patients, including children with Multisystem Inflammatory Syndrome in Children (MIS-C). TSS is typically caused by pathogenic superantigens stimulating excessive activation of the adaptive immune system. We show that SARS-CoV-2 spike contains sequence and structure motifs highly similar to those of a bacterial superantigen and may directly bind T cell receptors. We further report a skewed T cell receptor repertoire in COVID-19 patients with severe hyperinflammation, in support of such a superantigenic effect. Notably, the superantigen-like motif is not present in other SARS family coronaviruses, which may explain the unique potential for SARS-CoV-2 to cause both MIS-C and the cytokine storm observed in adult COVID-19.

Abstract
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.

Authors
Mary Hongying Cheng PhD, She Zhang PhD, Rebecca A. Porritt PhD, Magali Noval Rivas PhD, Lisa Paschold PhD, Edith Willscher PhD, Mascha Binder PhD, Moshe Arditi PhD, and Ivet Bahar PhD. Additional authors include Edith Willscher MSc and Mascha Binder MD.

Acknowledgements
We gratefully acknowledge support from NIH Awards P41 GM103712 (to I.B.) and R01 AI072726 (to M.A.), and useful comments from Drs. A. M. Brufsky, M. T. Lotze, S.-J. Gao, and S. D. Shapiro at the University of Pittsburgh Medical Center. We thank the clinical COVID-19 team at Halle for contributing samples to the Biobank.

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Oct 5 2020   Fetal Timeline   Maternal Timeline   News



A 3D structural model of the spike protein. The superantigenic region identified in this study is circled in yellow. A T cell receptor bound to the superantigen region is shown in cyan/red ribbon diagram. CREDIT Image courtesy of Ivet Bahar, PhD and Mary H Cheng, PhD.


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