Multi-omics approach identifies novel age-, time- and treatment-related immunopathological signatures in MIS-C and pediatric COVID-19
Keith Sacco; Riccardo Castagnoli; Svetlana Vakkilainen; Can Liu; Ottavia M. Delmonte; Cihan Oguz; Ian M. Kaplan; Sara Alehashemi; Peter D. Burbelo; Farzana Bhuyan; Adriana A. de Jesus; Kerry Dobbs; Lindsey B. Rosen; Aristine Cheng; Elana Shaw; Mikko S. Vakkilainen; Francesca Pala; Justin Lack; Yu Zhang; Danielle Fink; Vasileios Oikonomou; Andrew L. Snow; Clifton L. Dalgard; Jinguo Chen; Brian A. Sellers; Gina A. Montealegre Sanchez; Karyl Barron; Emma Rey; Maria Cecilia Vial; Maria Cecilia Poli; Amelia Licari; Daniela Montagna; Gian Luigi Marseglia; Francesco Licciardi; Ugo Ramenghi; Valentina Discepolo; Andrea Lo Vecchio; Alfredo Guarino; Eli M. Eisenstein; Luisa Imberti; Alessandra Sottini; Andrea Biondi; Sayonara Mato; Dana Gerstbacher; Meng Truong; Michael A. Stack; Mary Magliocco; Marita Bosticardo; Tomoki Kawai; Jefffrey J. Danielson; Tyler Hulett; Manor Askenazi; - NIAID Immune Response to COVID Group; - Chile MIS-C Group; - Pavia Pediatric COVID-19 Group; Jeffrey I Cohen; Helen C. Su; Douglas B. Kuhns; Michail S. Lionakis; Thomas M. Snyder; Steven M. Holland; Raphaela Goldbach-Mansky; John S. Tsang; Luigi D. Notarangelo.
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| PREPRINT-MEDRXIV | ID: ppmedrxiv-21263853
Pediatric COVID-19 (pCOVID-19) is rarely severe, however a minority of SARS-CoV-2-infected children may develop MIS-C, a multisystem inflammatory syndrome with significant morbidity. In this longitudinal multi-institutional study, we used multi-omics to identify novel time- and treatment-related immunopathological signatures in children with COVID-19 (n=105) and MIS-C (n=76). pCOVID-19 was characterized by enhanced type I IFN responses, and MIS-C by type II IFN- and NF-{kappa}B dependent responses, matrisome activation, and increased levels of Spike protein. Reduced levels of IL-33 in pCOVID-19, and of CCL22 in MIS-C suggested suppression of Th2 responses. Expansion of TRBV11-2 T-cell clonotypes in MIS-C was associated with inflammation and signatures of T-cell activation, and was reversed by glucocorticoids. The association of MIS-C with the combination of HLA A*02, B*35, C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load. Use of IVIG was identified as a confounding factor in the interpretation of autoantibody levels.
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