Superantigens and SARS-CoV-2

Abstract

It has been posited SARS-CoV-2 contains at least one unique superantigen-like motif not found in any other SARS or endemic coronaviruses. Superantigens are potent antigens that can send the immune system into overdrive. SARS-CoV-2 causes many of the biological and clinical consequences of a superantigen, and, in the context of reinfection and waning immunity, it is important to better understand the impact of a widely circulating, airborne pathogen that may be a superantigen, superantigen-like or trigger a superantigenic host response. Urgent research is needed to better understand the long-term risks being taken by governments whose policies enable widespread transmission of a potential superantigenic pathogen, and to more clearly define the vaccination and public health policies needed to protect against the consequences of repeat exposure to the pathogen.

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

“…Further examination of the TCR Vβ-binding region on the SARS-CoV-2 spike (T 678 NSPRRARSVASQ 690 ) also suggested strong structural similarities to the superantigenic fragment of staphylococcal SEB that has been recently identified to bind to CD28 costimulatory molecules, thus triggering an inflammatory cytokine storm [ 34 , 37 , 38 , 62 ]. However, the functional relevance of this putative SAg activity of the SARS-CoV-2 spike is presently unknown [ 63 ]. Here, we analysed the inflammatory activity of the SARS-CoV-2 spike on T cells in comparison with staphylococcal SEB.…”

“…To exclude the possibility that SARS-CoV-2 spike folding could interfere with the exposure of the TNSPRRAR SAg-like motif and the putative TCR/CD28 binding as well as the activation of CD4 + T cells [ 19 ], we also stimulated T cells with a heat-denatured SARS-CoV-2 spike (boiled) and we did not detect any significant change in the secretion of inflammatory cytokines compared to the native form ( Figure 2 g–j). Since the superantigen-like insert of the SARS-CoV-2 spike has been described to bind to CD28 costimulatory molecules [ 19 ], we tested the potential costimulatory activity of the SARS-CoV-2 spike to trigger second-order superantigenic responses [ 63 ] in anti-CD3 stimulated T cells. Consistent with previous data [ 41 , 44 ], a significant production of TNF-α ( Figure 3 a, mean = 1699 pg mL −1 ) and IL-2 ( Figure 3 b, mean = 638 pg mL −1 ) was only induced when CD3 and CD28 were co-engaged.…”

Staphylococcus aureus Infection-Related Glomerulonephritis with Dominant IgA Deposition

“…In contrast, the reported cases of IgA-IRGN developed due to infections that were caused by bacteria or viruses for which superantigens had not been confirmed, and it may thus not be possible to say that superantigens are involved in all IgA-IRGN cases. However, IgA-IRGN was recently confirmed in a patient with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [17], and SARS-CoV-2 was recently reported to cause many of the biological and clinical consequences of a superantigen [118]. Specific TCR-Vβ usage in an IgA-IRGN patient with a Chlamydia pneumonia infection was also detected [62].…”

Anergy in COVID-19 Infected and COVID-19 vaccinee

“…Like the state of normal human being in whom there are percentages of auto-reactive cells and autoantibodies that represent the baseline levels of normal physiological autoimmune reactions [29][30][31][32][33]. There are normal levels of anergic immune cells like anergic B, anergic T and anergic myeloid cells [9].…”

“…Sars cov-2 virus have an array of antigens; like spike, neucleocapsed membranous as well as nonstructural protein [Grifoni et al [29], Le Bert et al [30]. This virus appeared to have super-antigen, super-antigen like and/or super-antigen trigger host cytokine storm, lymphocyte differentiation, lymphocyte apoptosis, anergy and autoimmunity [31].…”