Molecular mimicry in multisystem inflammatory syndrome in children

Author:

Bodansky AaronORCID,Mettelman Robert C.ORCID,Sabatino Joseph J.,Vazquez Sara E.,Chou Janet,Novak TanyaORCID,Moffitt Kristin L.,Miller Haleigh S.,Kung Andrew F.,Rackaityte ElzeORCID,Zamecnik Colin R.ORCID,Rajan Jayant V.,Kortbawi Hannah,Mandel-Brehm Caleigh,Mitchell Anthea,Wang Chung-Yu,Saxena Aditi,Zorn KelseyORCID,Yu David J. L.,Pogorelyy Mikhail V.,Awad Walid,Kirk Allison M.ORCID,Asaki James,Pluvinage John V.ORCID,Wilson Michael R.ORCID,Zambrano Laura D.,Campbell Angela P.ORCID, ,Loftis Laura L.,Hobbs Charlotte V.,Tarquinio Keiko M.,Kong Michele,Fitzgerald Julie C.,Espinal Paula S.,Walker Tracie C.,Schwartz Stephanie P.,Crandall Hillary,Irby Katherine,Staat Mary Allen,Rowan Courtney M.,Schuster Jennifer E.,Halasa Natasha B.,Gertz Shira J.,Mack Elizabeth H.,Maddux Aline B.,Cvijanovich Natalie Z.,Zinter Matt S.,Thomas Paul G.ORCID,Randolph Adrienne G.,Anderson Mark S.ORCID,DeRisi Joseph L.ORCID

Abstract

AbstractMultisystem 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.

Publisher

Springer Science and Business Media LLC

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