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.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-kappa B-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.

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

Delmonte, Ottavia M;Licciardi, Francesco;Ramenghi, Ugo;Biondi, Andrea;Bosticardo, Marita;
2022-01-01

Abstract

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.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-kappa B-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.
2022
28
5
1050
1062
Child; Humans; SARS-CoV-2; Systemic Inflammatory Response Syndrome; T-Lymphocytes; COVID-19
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
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1877961
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