SARS-CoV-2 Spike Does Not Possess Intrinsic Superantigen-like Inflammatory Activity

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a rare hyperinflammatory disease occurring several weeks after SARS-CoV-2 infection. The clinical similarities between MIS-C and the toxic shock syndrome, together with the preferential expansion of T cells with a T-cell receptor variable β chain (TCRVβ) skewing, suggested a superantigen theory of MIS-C. For instance, recent in silico modelling evidenced the presence of a highly conserved motif within SARS-CoV-2 spike protein similar in structure to the superantigenic fragment of staphylococcal enterotoxin B (SEB). However, experimental data on the superantigenic activity of the SARS-CoV-2 spike have not yet been provided. Here, we assessed the superantigenic activity of the SARS-CoV-2 spike by analysing inflammatory cytokine production in both Jurkat cells and the peripheral blood CD4+ T cells stimulated with the SARS-CoV-2 spike or SEB as a control. We found that, unlike SEB, the SARS-CoV-2 spike does not exhibit an intrinsic superantigen-like activity.

Bivalent binding of staphylococcal superantigens to the TCR and CD28 triggers inflammatory signals independently of antigen presenting cells

“…To verify the functional relevance of our computational simulations, we performed a kinetic analysis of inflammatory cytokine secretion in culture supernatants of highly purified (> 95%) primary CD4 + T cells ( Supplementary Figures S1A, B ) stimulated with SEB alone. Consistently with our previous data ( 27 , 43 ), CD4 + T cells isolated from the peripheral blood of healthy donors (HD) expressed CD28 (mean ± SEM = 96.37 ± 2.41) but neither HLA-DR (mean ± SEM = 3.1 ± 0.9) nor B7.1/CD80 (mean ± SEM = 0.98 ± 0.59) nor B7.2/CD86 (mean ± SEM = 1.81 ± 0.88). Stimulation of CD4 + T cells with SEB alone induced a strong production of IFN-γ ( Figure 3A ), IL-2 ( Figure 3B ), IL-6 ( Figure 3C ), TNF-α ( Figure 3D ), IL-17A ( Figure 3E ), IL-22 ( Figure 3F ) and GM-CSF ( Figure 3G ) after 48-72 hours.…”

A systems approach evaluating the impact of SARS-CoV-2 variant of concern mutations on CD8+ T cell responses

“…The Wuhan Hu-1 sequences of these epitopes contain ‘PRRA’, which is a motif forming a core of a hypothesised and controversial SARS-CoV-2 ‘superantigen’ [ 26 , 27 ]. This so-called ‘SARS-CoV-2 superantigen’ has been hypothesised to play a role in post-COVID-19 multisystem inflammatory syndrome [ 20 , 23 ], although a recent study found no evidence for its ‘intrinsic superantigen-like inflammatory activity’ [ 36 , 37 ]. In fact, 9/15 (60%) pMHC-I containing this hypothesised superantigen core are predicted to become ‘nonbinders’ as a result of BA.1 mutation ( Fig.…”

Safety of COVID-19 Vaccines in Patients with Autoimmune Diseases, in Patients with Cardiac Issues, and in the Healthy Population

“…This superantigen effect of Spike could explain “ multi-system inflammatory syndrome ” (MIS-C) in children/adolescents after COVID-19, a phenomenon observed also after COVID-19 vaccines [ 155 , 156 , 157 , 158 , 159 ]. However, a recent paper demonstrated that Spike is not able to act as a superantigen in human cell lines in vitro [ 160 ]. It will be interesting to ascertain the effect of smaller parts of the Spike protein in regard to their possible cytotoxic effect to understand what is causing such high inflammation.…”