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Molecular mimicry in multisystem inflammatory syndrome in children
Aaron Bodansky1, Robert C Mettelman2, Joseph J Sabatino3,4
1Department of Pediatrics, Division of Critical Care, University of California San Francisco, San Francisco, CA, USA.
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.
Insights
Multisystem inflammatory syndrome in children (MIS-C) results from SARS-CoV-2 infection. Autoantibodies target the SNX8 protein, potentially due to molecular mimicry with the viral nucleocapsid, explaining MIS-C
Area of Science:
- Immunology
- Virology
- Pediatrics
Background:
- Multisystem inflammatory syndrome in children (MIS-C) is a severe post-infectious complication of SARS-CoV-2.
- The underlying pathophysiological mechanisms linking SARS-CoV-2 infection to MIS-C remain largely unknown.
Purpose of the Study:
- To elucidate the molecular mechanisms driving MIS-C pathogenesis.
- To identify specific host proteins targeted by autoantibodies in MIS-C patients.
- To investigate the relationship between SARS-CoV-2 infection and autoimmune responses.
Main Methods:
- Analysis of a large sample set from MIS-C patients.
- Identification of host proteins targeted by patient autoantibodies, focusing on SNX8.
- Probing antibody responses to the SARS-CoV-2 proteome, particularly the nucleocapsid protein.
- Assessment of T cell cross-reactivity between viral and host protein epitopes.
Main Results:
- A distinct set of host proteins, including SNX8, were identified as targets of autoantibodies in MIS-C patients.
- Enriched antibody reactivity was observed against a specific domain of the SARS-CoV-2 nucleocapsid protein.
- Remarkable sequence similarity was found between immunogenic regions of the SARS-CoV-2 nucleocapsid and host SNX8 proteins.
- Cross-reactive T cells recognizing both SNX8 and SARS-CoV-2 nucleocapsid epitopes were identified in many MIS-C patients.
Conclusions:
- MIS-C is associated with a specific immune response to the SARS-CoV-2 nucleocapsid protein.
- Molecular mimicry between the viral nucleocapsid and host SNX8 protein may drive autoimmunity in MIS-C.
- These findings provide a mechanistic link between SARS-CoV-2 infection and the inflammatory syndrome in MIS-C.
- The study offers insights into the pathogenesis of post-infectious autoinflammatory diseases.
