Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a febrile pediatric inflammatory disease that may develop weeks after initial SARS-CoV-2 infection or exposure. MIS-C involves systemic hyperinflammation and multiorgan involvement, including severe cardiovascular, gastrointestinal (GI) and neurological symptoms. Some clinical attributes of MIS-C—such as persistent fever, rashes, conjunctivitis and oral mucosa changes (red fissured lips and strawberry tongue)—overlap with features of Kawasaki disease (KD). In addition, MIS-C shares striking clinical similarities with toxic shock syndrome (TSS), which is triggered by bacterial superantigens (SAgs). The remarkable similarities between MIS-C and TSS prompted a search for SAg-like structures in the SARS-CoV-2 virus and the discovery of a unique SAg-like motif highly similar to a Staphylococcal enterotoxin B (SEB) fragment in the SARS-CoV-2 spike 1 (S1) glycoprotein. Computational studies suggest that the SAg-like motif has a high affinity for binding T-cell receptors (TCRs) and MHC Class II proteins. Immunosequencing of peripheral blood samples from MIS-C patients revealed a profound expansion of TCR β variable gene 11-2 (TRBV11-2), which correlates with MIS-C severity and serum cytokine levels, consistent with a SAg-triggered immune response. Computational sequence analysis of SARS-CoV-2 spike further identified conserved neurotoxin-like motifs which may alter neuronal cell function and contribute to neurological symptoms in COVID-19 and MIS-C patients. Additionally, autoantibodies are detected during MIS-C, which may indicate development of post-SARS-CoV-2 autoreactive and autoimmune responses. Finally, prolonged persistence of SARS-CoV-2 RNA in the gut, increased gut permeability and elevated levels of circulating S1 have been observed in children with MIS-C. Accordingly, we hypothesize that continuous and prolonged exposure to the viral SAg-like and neurotoxin-like motifs in SARS-CoV-2 spike may promote autoimmunity leading to the development of post-acute COVID-19 syndromes, including MIS-C and long COVID, as well as the neurological complications resulting from SARS-CoV-2 infection.

Liquid biomarkers of macrophage dysregulation and circulating spike protein illustrate the biological heterogeneity in patients with post-acute sequelae of COVID-19

“…Notably, S1 levels did numerically correlate with SARS-CoV-2 antibody titers but not with any of the analyzed soluble immune factors. Nevertheless, a few individuals with circulating S1 had relatively high plasma levels of TNF, IL-1β, IL-6 and/or IL-8 supporting the superantigenic features of the spike protein [13]. In line with a recent publication analyzing 31 PASC patients [17], this data suggests that individuals with PASC that have circulating S1 represent a different disease subset independent of monocyte/macrophage reprogramming.…”

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

“…Interestingly, the Wuhan Hu-1 sequences of these epitopes contain ‘PRRA’, which is a key motif forming a putative core of a hypothesised SARS-CoV- 2 ‘superantigen’ with structural similarities to the prototypical superantigen - staphylococcal enterotoxin B (SEB)[26,27]. This SARS-CoV-2 superantigen is hypothesised to play a role in post-COVID-19 multisystem inflammatory syndrome and the recent rise in children with severe acute hepatitis[20,23]. In fact, 9/15 (60%) pMHC-I containing this hypothesised superantigen core are predicted to become ‘nonbinders’ as a result of BA1 mutation (Fig 2E, Table 2).…”

“…There are ongoing efforts to characterise disorders that are considered ‘post-COVID’ complications, ranging from so-called long-COVID [21,22,55–58] to broad inflammatory disease [20,23–25]. A leading hypothesis underpinning observations of multisystem inflammatory disorder and severe acute hepatitis, is that a theoretical SARS-CoV-2 superantigen promotes aberrant T cell activation [20,23]. The ‘PRRA’ motif, part of the hypothesised core of a SARS-CoV-2 superantigen [26,27] overlays three CD8+ T cell epitopes that have mutations in BA1 Omicron.…”

“…Adding to this heterogeneous landscape, is that although many individuals now experience COVID-19 with mild symptoms, there are increasing reports of complications following SARS-CoV-2 infection. For example, considerable numbers of individuals suffer with post- acute sequalae of COVID-19[20–22] (long COVID) and there are increasing reports of multisystem inflammatory disorders and severe acute hepatitis, where SARS-CoV-2 has been implicated as the causative agent [20,23–25]. Indeed, while T cells are thought to provide a barrier against Omicron infection where antibody responses are evaded, there is increasing evidence that T cells may on the other hand contribute to post-COVID complications in some individuals, e.g., through provoking inflammatory disorders[20,23,26,27], elevated T cell exhaustion in long COVID[21] and CD8+ T cell infection and lymphopenia following SARS- CoV-2 exposure [28].…”

The results of a unique dietary supplement (nutraceutical formulation) used to treat the symptoms of long-haul COVID

“…The exact underlying cause of long-COVID remains uncertain, but most reports agree that this condition is associated with a persistent viral infection and long-lasting inflammation ( 6 , 7 ). Specific neurological symptoms (fatigue, brain fog, anosmia, and ageusia/dysgeusia) in long COVID resemble “sickness behavior,” a response of the autonomic nervous system to pro-inflammatory cytokines ( 8 ).…”