The identification of a SARs-CoV2 S1 protein derived peptide with super-antigen-like stimulatory properties on T-cells

Severe COVID-19 is characterized by a cytokine-mediated acute respiratory distress syndrome resembling toxic shock syndrome. We identified a SARS-CoV-2 S1 spike peptide (P3) with sequence homology to bacterial super-antigens. Computational modelling revealed P3 binding to MHC class I/II and TCR regions that partially overlap with staphylococcal enterotoxin B (SEB) and enterotoxin H (SEH) binding sites. In vitro, P3 potently activated 25-40% of human CD4 and CD8 T cells, accompanied by the increased expression of effector molecules IFNg and granzyme B. In vivo, P3 peptide administration to mice induced an inflammatory response characterized by elevated levels of proinflammatory cytokines, IL1b, IL6 and TNFa. Further, the P3 peptide promoted a more robust in vitro immune response of T-cells from COVID-19 patients with severe disease, as evidenced by increased CD69 and IFNg expression. Consistent with its super-antigenic properties, P3 preferentially also expanded T cells bearing restricted TCR Vα and Vβ chain repertoires in vitro. Overall, the homology of the P3 peptide to several endogenous mammalian proteins suggests the potential for the future discovery of related peptides that may contribute to inflammation and autoimmune disorders in humans.