Evidence of molecular mimicry in multisystem inflammatory syndrome in children (MIS-C)

Authors

• Aaron Bodansky, UCSF
• Robert Mettelman, St. Jude Children's Research Hospital
• Joseph Sabatino, University of California, San Francisco
• Sara Vazquez, University of California San Francisco Medical Center
• Janet Chou, Harvard Medical School
• Tanya Novak, Harvard Medical School
• Kristin Moffitt, Harvard Medical School
• Haleigh Miller, University of California San Francisco Medical Center
• Andrew Kung, University of California San Francisco Medical Center
• Elze Rackaityte, University of California San Francisco Medical Center
• Colin Zamecnik, University of California San Francisco Medical Center
• Jayant Rajan, University of California San Francisco Medical Center
• Hannah Kortbawi, University of California San Francisco Medical Center
• Caleigh Mandel-Brehm, University of California San Francisco Medical Center
• Anthea Mitchell, CZ Biohub
• Chung-Yu Wang, CZ Biohub
• Aditi Saxena, CZ Biohub
• Kelsey Zorn, University of California San Francisco Medical Center
• David Yu, University of California, San Francisco
• Mikhail Pogorelyy, St. Jude Children's Research Hospital
• Walid Awad, St. Jude Children's Research Hospital
• Allison Kirk, St. Jude Children's Research Hospital
• John Pluvinage, University of California San Francisco Medical Center
• Michael Wilson, University of California San Francisco Medical Center
• Laura Loftis, Baylor College of Medicine
• Charlotte Hobbs, University of Mississippi Medical Center
• Keiko Tarquinio, Emory University
• Michelle Kong, University of Alabama at Birmingham
• Julie Fitzgerald, Children's Hospital of Philadelphia
• Paula Espinal, Miami Children's Hospital
• Tracie Walker, University of North Carolina
• Stephanie Schwartz, University of North Carolina
• Hillary Crandall, University of Utah
• Katherine Irby, Arkansas Children's Hospital
• Mary Staat, Cincinnati Children's Hospital Medical Center
• Courtney Rowan, Riley Hospital for Children
• Jennifer Schuster, Children's Mercy Hospital
• Natasha Halasa, Vanderbilt University Medical Center
• Shira Gertz, Saint Barnabas Medical Center
• Elizabeth Mack, Medical University of South Carolina
• Aline Maddux, University of Colorado Anschutz Medical Campus
• Natalie Cvijanovich, University of California, San Francisco
• Matt Zinter, University of California San Francisco Medical Center
• Laura Zambrano, Centers for Disease Control and Prevention
• Angela Campbell, Centers for Disease Control and Prevention
• Paul Thomas, St. Jude Children's Research Hospital
• Adrienne Randolph, Harvard Medical School
• Mark Anderson, University of California San Francisco Medical Center
• Joseph DeRisi, University of California San Francisco Medical Center

Author ORCID

Aaron Bodansky 0000-0001-8943-8233

Publication Date

5-9-2024

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of MIS-C patient samples (n=199) to identify a distinct set of host proteins that are differentially targeted by patient autoantibodies relative to matched controls. We identified an autoreactive epitope within SNX8, a protein expressed primarily in immune cells that regulates an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed the SARS-CoV-2 proteome-wide MIS-C patient antibody response and found it to be differentially reactive to a distinct domain of the SARS-CoV-2 nucleocapsid (N) protein relative to controls. This viral N region and the mapped SNX8 epitope bear remarkable biochemical similarity. Furthermore, we find that many children with anti-SNX8 autoantibodies also have T cells cross-reactive to both SNX8 and this distinct region of the SARS-CoV-2 N protein. Together, these findings suggest that MIS-C patients develop a characteristic immune response against the SARS-CoV-2 N protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link from the infection to the inflammatory syndrome with implications for better understanding a range of post-infectious autoinflammatory diseases.

Keywords

PhIP-Seq, MIS-C, Molecular mimicry

Repository

Dryad

Distribution License

CC0 1.0 Universal - No copyright; this work is in the public domain

Access Instructions

This data is public domain under the CC-0.0 License