Identifying mechanisms of immune dysregulation via severe pediatric SARS-CoV-2

Project Summary/Abstract This proposal presents a five year research career development program focused on the mechanisms by which a dysregulated adaptive immune response to SARS-CoV-2 infection leads particular children to become critically ill. The candidate is currently a Pediatric Critical Care Medicine (PCCM) clinical fellow at the University of California, San Francisco (UCSF) and has been appointed Assistant Professor of Pediatrics at UCSF beginning July 1, 2024. The outlined proposal builds on the candidate's previous research and clinical experience caring for, and studying, children with multisystem inflammatory syndrome in children (MIS-C), a severe and enigmatic post-SARS-CoV-2 inflammatory disease. It integrates the synergistic expertise of co- mentors Joseph DeRisi and Mark Anderson in state-of-the-art functional genomic technologies for immune profiling and mechanisms of autoimmune disease. The proposed experiments and training will position the candidate with a unique set of cross disciplinary skills that will enable his transition to independence as a physician scientist studying mechanisms of immune dysregulation in pediatric critical illness. Immune dysregulation is increasingly recognized as underlying a wide range of critical illness in children. Efforts to treat these conditions are limited by a lack of diagnostic clarity or targeted therapies, underpinned by gaps in knowledge of the specific mechanisms by which infections precipitate immune dysregulation. Previous work studying adults with COVID19 revealed that unrecognized autoantibodies predispose certain individuals to critical illness. However, in part because severe pediatric SARS-CoV-2 related disease is so rare, a detailed mechanistic understanding of what causes certain children to be particularly vulnerable remains lacking. The foundation of this proposal are preliminary studies which leveraged state-of-the-art technologies to identify a set of novel autoantibodies specific to children with MIS-C, and the related discovery of cross-reactive B and T cells between SARS-CoV-2 and the antiviral host protein SNX8. Whether additional novel autoantibodies contribute to a wider range of severe pediatric SARS-CoV-2 related diseases, and how cross-reactive adaptive immune responses lead to MIS-C, are questions addressed in this proposal. The aims are: 1) Define and characterize the autoantibody repertoire in children with severe SARS-CoV-2 disease and, 2) Determine the biological consequences of cross-reactivity in MIS-C. The scientific objective of this proposal is to elucidate specific mechanisms by which certain children, either by harboring pre-existing autoantibodies or generating cross-reactive adaptive immune responses, develop critical illness from common infections. The results will inform subsequent studies: a) establishing pathogenicity of these autoreactivities through organoid and murine models, b) building diagnostics to identify vulnerable children and targeted therapies to treat them, and c) translation of the immune profiling platform developed in this proposal into additional disease contexts.