Molecular mimicry in multisystem inflammatory syndrome in children

Nature. 2024 Aug;632(8025):622-629. doi: 10.1038/s41586-024-07722-4. Epub 2024 Aug 7.

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection1,2, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases.

MeSH terms

  • Antibodies, Viral* / immunology
  • Autoantibodies* / immunology
  • COVID-19* / complications
  • COVID-19* / immunology
  • COVID-19* / virology
  • Child
  • Coronavirus Nucleocapsid Proteins / chemistry
  • Coronavirus Nucleocapsid Proteins / immunology
  • Cross Reactions* / immunology
  • Epitopes* / chemistry
  • Epitopes* / immunology
  • Humans
  • Molecular Mimicry* / immunology
  • Phosphoproteins / chemistry
  • Phosphoproteins / immunology
  • SARS-CoV-2* / chemistry
  • SARS-CoV-2* / immunology
  • SARS-CoV-2* / metabolism
  • SARS-CoV-2* / pathogenicity
  • Sorting Nexins / chemistry
  • Sorting Nexins / immunology
  • Systemic Inflammatory Response Syndrome* / immunology
  • Systemic Inflammatory Response Syndrome* / pathology
  • Systemic Inflammatory Response Syndrome* / virology
  • T-Lymphocytes / immunology

Substances

  • Antibodies, Viral
  • Autoantibodies
  • Coronavirus Nucleocapsid Proteins
  • Epitopes
  • nucleocapsid phosphoprotein, SARS-CoV-2
  • Phosphoproteins
  • SNX8 protein, human
  • Sorting Nexins

Supplementary concepts

  • pediatric multisystem inflammatory disease, COVID-19 related