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

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

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