In the later stages of COVID-19, SARS-CoV-2 proceeds to infect the lower respiratory tract, causing viral pneumonitis and, in severe cases, systemic coagulopathy and hyperinflammation. This hyperinflammatory state has similarities to the toxic shock syndrome caused by superantigens (SAgs). SAgs, which are usually found in unprocessed bacterial toxins, bind directly to an MHC molecule and one of the variable domains of the T cell receptor (TCR), and this cross-linking leads to an excessive release of inflammatory cytokines. Previous in silico analyses have identified a SAg motif adjacent to the S1–S2 cleavage site of SARS-CoV-2 spike (S) glycoprotein, which has a sequence and structure similar to staphylococcal enterotoxin B (SEB). In addition, TCR Vβ skewing, which is indicative of SAg-mediated T cell activation, has been observed in patients with COVID-19 who have severe hyperinflammation.

This preprint (non-peer-reviewed) by Cheng et al. further characterizes the SAg motif in SARS-CoV-2 S protein and evaluates a monoclonal antibody capable of targeting this region. Molecular docking simulations confirmed that the SAg motif of S protein fits into the catalytic cavities of transmembrane protease serine 2 (TMPRSS2) and furin, which stabilizes S before S1–S2 cleavage. Given the homology of this motif with SEB, antibodies to SEB were screened in silico for their ability to bind the SAg motif on S protein. The monoclonal antibody 6D3 engaged S with a binding affinity comparable to that of TMPRSS2 and furin and was capable of inhibiting infection with live SARS-CoV-2, as assessed by immunofluorescent staining of double-stranded RNA and S in Vero-E6 cells.

Most SARS-CoV-2 neutralizing antibodies isolated from convalescent patients have been identified using recombinant S proteins with a mutated S1–S2 cleavage site. This helps to stabilize the S trimer but fails to capture antibodies that bind to the cleavage site and potentially the adjacent SAg motif. Viral challenge studies in vivo will be necessary for the clinical translation of SAg-targeting antibodies. Furthermore, ex vivo stimulation of patient T cells with SARS-CoV-2 S protein and SEB will be needed to confirm the possibility of SAg-mediated T cell activation in patients with severe COVID-19. Nonetheless, monoclonal antibodies targeting the S protein cleavage site are potentially capable of virus neutralization and mitigation of shock following infection with SARS-CoV-2 and other human coronaviruses that encode furin-like cleavage sites, specifically MERS, HKU1 and OC43.