Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19

• Published in: Nature medicine Vol. 28; no. 5; pp. 1050 - 1062
• Main Authors: Sacco, Keith, Castagnoli, Riccardo, Vakkilainen, Svetlana, Liu, Can, Delmonte, Ottavia M., Oguz, Cihan, Kaplan, Ian M., Alehashemi, Sara, Burbelo, Peter D., Bhuyan, Farzana, de Jesus, Adriana A., Dobbs, Kerry, Rosen, Lindsey B., Cheng, Aristine, Shaw, Elana, Vakkilainen, Mikko S., Pala, Francesca, Lack, Justin, Zhang, Yu, Fink, Danielle L., Oikonomou, Vasileios, Snow, Andrew L., Dalgard, Clifton L., Chen, Jinguo, Sellers, Brian A., Montealegre Sanchez, Gina A., Barron, Karyl, Rey-Jurado, Emma, Vial, Cecilia, Poli, Maria Cecilia, Licari, Amelia, Montagna, Daniela, Marseglia, Gian Luigi, Licciardi, Francesco, Ramenghi, Ugo, Discepolo, Valentina, Lo Vecchio, Andrea, Guarino, Alfredo, Eisenstein, Eli M., Imberti, Luisa, Sottini, Alessandra, Biondi, Andrea, Mató, Sayonara, Gerstbacher, Dana, Truong, Meng, Stack, Michael A., Magliocco, Mary, Bosticardo, Marita, Kawai, Tomoki, Danielson, Jeffrey J., Hulett, Tyler, Askenazi, Manor, Hu, Shaohui, Cohen, Jeffrey I., Su, Helen C., Kuhns, Douglas B., Lionakis, Michail S., Snyder, Thomas M., Holland, Steven M., Goldbach-Mansky, Raphaela, Tsang, John S., Notarangelo, Luigi D.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2022; Nature Publishing Group
• Subjects: 631/208/514/1949; 631/250/256; 631/326/596/4130; 692/420/2780; 692/699/255/2514; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell activation; Child; Children; Coronaviruses; COVID-19; COVID-19 - complications; COVID-19 - genetics; Gene expression; Histocompatibility antigen HLA; Humans; Infectious Diseases; Inflammation; Interferon; Lymphocytes; Lymphocytes B; Lymphocytes T; Metabolic Diseases; Molecular Medicine; Morbidity; Multisystem inflammatory syndrome in children; Mutation; Mutation rates; Neurosciences; NF-κB protein; Pediatrics; Proteins; Proteomics; Respiratory diseases; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Spike protein; Systemic Inflammatory Response Syndrome - genetics; T-Lymphocytes; Transcriptomics; Viral diseases
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-022-01724-3

Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 ( n  = 110) and MIS-C ( n  = 76), along with pediatric healthy controls (pHCs; n  = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy. Transcriptomic, proteomic and immune repertoire profiling reveals distinct peripheral features of MIS-C and pediatric COVID-19, including elevated soluble spike protein levels, more pronounced type II IFN-dependent gene expression and a higher B cell mutation rate in patients with MIS-C.