Molecular mimicry in multisystem inflammatory syndrome in children

Aaron Bodansky, Robert C. Mettelman, Joseph J. Sabatino, Sara E. Vazquez, Janet Chou, Tanya Novak, Kristin L. Moffitt, Haleigh S. Miller, Andrew F. Kung, Elze Rackaityte, Colin R. Zamecnik, Jayant V. Rajan, Hannah Kortbawi, Caleigh Mandel-Brehm, Anthea Mitchell, Chung-Yu Wang, Aditi Saxena, Kelsey Zorn, David J. L. Yu, Mikhail V. Pogorelyy, Walid Awad, Allison M. Kirk, James Asaki, John V. Pluvinage, Michael R. Wilson, Laura D. Zambrano, Angela P. Campbell, Paul G. Thomas, Adrienne G. Randolph, Mark S. Anderson () and Joseph L. DeRisi ()
Additional contact information
Aaron Bodansky: University of California San Francisco
Robert C. Mettelman: St. Jude Children’s Research Hospital
Joseph J. Sabatino: University of California San Francisco
Sara E. Vazquez: University of California San Francisco
Janet Chou: Department of Pediatrics
Tanya Novak: Boston Children’s Hospital
Kristin L. Moffitt: Harvard Medical School
Haleigh S. Miller: University of California San Francisco
Andrew F. Kung: University of California San Francisco
Elze Rackaityte: University of California San Francisco
Colin R. Zamecnik: University of California San Francisco
Jayant V. Rajan: University of California San Francisco
Hannah Kortbawi: University of California San Francisco
Caleigh Mandel-Brehm: University of California San Francisco
Anthea Mitchell: Chan Zuckerberg Biohub SF
Chung-Yu Wang: Chan Zuckerberg Biohub SF
Aditi Saxena: Chan Zuckerberg Biohub SF
Kelsey Zorn: University of California San Francisco
David J. L. Yu: University of California San Francisco
Mikhail V. Pogorelyy: St. Jude Children’s Research Hospital
Walid Awad: St. Jude Children’s Research Hospital
Allison M. Kirk: St. Jude Children’s Research Hospital
James Asaki: University of California San Francisco
John V. Pluvinage: University of California San Francisco
Michael R. Wilson: University of California San Francisco
Laura D. Zambrano: Centers for Disease Control and Prevention
Angela P. Campbell: Centers for Disease Control and Prevention
Paul G. Thomas: St. Jude Children’s Research Hospital
Adrienne G. Randolph: Harvard Medical School
Mark S. Anderson: University of California San Francisco
Joseph L. DeRisi: University of California San Francisco

Nature, 2024, vol. 632, issue 8025, 622-629

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07722-4

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