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A study from the University of Pittsburgh School of Medicine and Cedars-Sinai addresses a mystery first raised in March: Why do some people with COVID-19 develop severe inflammation? The research shows how the molecular arrangement and arrangement of the SARS-CoV-2 spike protein–part of the virus that causes COVID-19–could be behind the inflammatory syndrome cropping up in infected patients.
Indicators of a newly identified condition in pediatric COVID-19 patients, known as Multisystem Inflammatory Syndrome in Children (MIS-C), include persistent fever and acute inflammation that can affect a host of bodily systems. While rare, the syndrome can be serious or even deadly.
The first reports of this condition coming out of Europe caught the attention of study co-senior author Moshe Arditi, M.D., director of the Pediatric Infectious Diseases and Immunology Division at Cedars-Sinai and a specialist on a different pediatric inflammatory disease–Kawasaki disease.
Arditi contacted his long-time collaborator, Ivet Bahar, Ph.D., distinguished professor and John K. Vries Chair of computational and systems biology at Pitt School of Medicine, and 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 the receptors on human T cells, the foot soldiers of the immune system.
Under normal circumstances, T cells help the body fight off infection, but when these cells are activated in abnormally large amounts, as is the case with superantigens, they create massive amounts of inflammatory cytokines–small proteins involved in immune system signaling–in what’s called a”cytokine storm.”
Using this computer version, the group was able to find that a specific area on the spike protein with superantigenic features interacts with T cells. Then, they compared this area to a bacterial protein that causes toxic shock syndrome and found striking similarities in both sequence and structure. Importantly, the proposed SARS-CoV-2 superantigen revealed a high affinity for binding T cell receptors–the first step toward touching off a runaway immune response.
“Everything arrived one after another, whenever a huge surprise. The pieces of the mystery ended up fitting extremely well,” said Bahar, co-senior author on the study.
By discovering protein-level similarities between SARS-CoV-2 and the bacterial structure that causes toxic shock syndrome, the researchers said they may have opened up new avenues for treating not only MIS-C patients, but also adults with COVID-19 disease experiencing cytokine storm.
The researchers collaborated with scientists studying adult COVID-19 patients in Germany and found that those who experienced acute symptoms had a T cell response similar to what’s seen in people exposed to superantigens and quite different from the T cell response in patients who had only mild symptoms.
Arditi’s and Bahar’s labs are now using the ideas generated by this research to search for and test antibodies specific to the SARS-CoV-2 superantigen, with the objective of developing therapies that specifically address MIS-C and cytokine storm in COVID-19 patients.
University of Pittsburgh
Cheng, M. H., et al. (2020) Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation. Proceedings of National Academy of Sciences. doi.org/10.1073/pnas.2010722117.
