MIS-C in children after COVID-19: Origin in the gut?

Multisystemic inflammatory syndrome can appear in children and adolescents as a consequence of SARS-CoV-2 infection.

Post-acute COVID-19 symptoms have similarities to toxic shock syndrome

The clinical features of MIS-C overlap to some extent with Kawasaki syndrome, which has been known for some time. In addition to the persistent fever, MIS-C presents with a rash, changes in the oral mucosa and conjunctivitis. The lips can be red and chapped, the tongue strawberry-coloured. In these symptoms, MIS-C is similar to Kawasaki syndrome. However, there is also further overlap with toxic shock syndrome (TSS). The latter is triggered by bacterial superantigens (SAgs). In TSS, staphylococcal or streptococcal exotoxins can lead to high fever, arterial hypotension and diffuse erythematous rashes. As with MIS-C, multiorgan failure can occur with TSS.1

Bacterial superantigens and the glycoprotein spike 1 are strikingly similar

Similarities in the symptomatology of both syndromes can be explained at the molecular level by the following theory and observations: The SARS-CoV-2 virus has SAg-like structures. In the glycoprotein spike 1 (S1) region of SARS-CoV-2, a motif was discovered that is very similar to a fragment of staphylococcal enterotoxin B (SEB). Computational studies suggest that SAg-like motifs have a high affinity for binding T-cell receptors (TCRs) and MHC class II proteins.

Further investigations using immunosequencing of peripheral blood samples from MIS-C patients confirmed this theory. Here, a strong expansion of the variable TCR-β gene 11-2 (TRBV11-2) was shown. This expansion correlated positively with the severity of the multisystemic inflammatory syndrome (MIS-C). This immunological observation is consistent with an SAg-triggered immune response. Moreover, autoantibodies could be isolated in the affected patients. This is an important indication of post-acute autoimmunity following SARS-CoV-2 infection.1

What is the role of the gut in SARS-CoV-2 and MIS-C?

In children with MIS-C, a prolonged persistence of SARS-CoV-2 RNA in the gut was observed. At the same time, the children suffered from increased intestinal permeability. Increased levels of circulating S1 (glycoprotein spike 1) could be measured in the children. The research group hypothesised that continuous exposure to the viral SAg-like motifs in the glycoprotein spike 1 (S1) region may promote autoimmunity. In addition to the viral SAg-like motifs, neurotoxin-like motifs have also been reported in SARS-CoV-2. These two motifs may contribute to the development of post-acute COVID-19 syndromes, such as MIS-C and Long-COVID.1

  1. Noval Rivas M. et al. (2022). Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis. Front Immunol. 2022 Jul 7;13:941009.