SARS-CoV-2 spike superantigenic character and neutralization strategies 

A hyperinflammatory syndrome reminiscent of toxic shock syndrome is observed in severe COVID-19 patients, including children with Multisystem Inflammatory Syndrome in Children (MIS-C). Our recent work1 showed that the SARS-CoV-2 spike contains a motif highly similar to that of a bacterial superantigen, Staphylococcal enterotoxin B (SEB), known to cause such a toxic shock. Notably, this superantigen-like motif is not present in other SARS family coronaviruses, which may explain the unique potential for SARS-CoV-2 to cause MIS-C in children and a cytokine storm in adults and the significance of immuno-modulating therapies in COVID-19. A skewed T cell receptor repertoire observed in COVID-19 patients with severe hyperinflammation supports such a superantigenic effect1,2. Furthermore a monoclonal antibody known to neutralize SEB inhibits infection in live virus assays3. This and other current antibody treatments and potential repurposable drugs4 are discussed in the light of newly emerging variants of concern5.

1. Cheng MH, Zhang S, Porritt RA, Rivas MN, Paschold L, Willscher E, Binder M, Arditi M, Bahar I (2020) Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation. Proc Natl Acad Sci USA 117: 25254-25262
2. Porritt RA, Paschold L, Noval Rivas M, Cheng MH, Yonker LM, Chandnani H, Lopez M, Simnica D, Schultheiß C, Santiskulvong C, van Eyk J, McCormick JK, Fasano A, Bahar I, Binder M, Arditi M (2021) HLA class I-associated expansion of TRBV11-2 T cells in Multisystem Inflammatory Syndrome in Children. J Clin Invest. 131(10): e146614
3. Cheng MH, Porritt RA, Rivas MN, Krieger JM, Ozdemir AB, Garcia G Jr, Arumugaswami V, Fries BC, Arditi M, Bahar I. (2021) A monoclonal antibody against staphylococcal enterotoxin B superantigen inhibits SARS-CoV-2 entry in vitro. Structure. 29(9):951-962
4. Chen F, Shi Q, Pei F, Vogt A, Porritt RA, Garcia G, Gomez AC, Cheng MH, Schurdak ME, Chan SY, Arumugaswami V, Stern AM, Taylor DL, Arditi M, Bahar I. (2021) A Systems-level Study Reveals Host-targeted Repurposable Drugs Against SARS-CoV2 Infection. Mol Systems Biol. 17:e10239
5. Cheng MH, Krieger JM, Banerjee A, Xiang Y, Kaynak B, Shi Y, Arditi M, Bahar I (2022) Impact of new variants on SARS-CoV-2 infectivity and neutralization: A molecular assessment of the alterations in the spike-host protein interactions. iScience 25(3):103939

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