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

2022; Nature Portfolio; Volume: 28; Issue: 5 Linguagem: Inglês

10.1038/s41591-022-01724-3

1546-170X

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 S. Barron, Emma Rey-Jurado, Cecilia Vial, M. 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 Mató, Dana Gerstbacher, Meng Truong, Michael Stack, Mary Magliocco, Marita Bosticardo, Tomoki Kawai, Jeffrey J. Danielson, Tyler Hulett, Manor Askenazi, Shaohui Hu, Jason Barnett, Xi Cheng, Krishnaveni Kaladi, Vasudev Kuram, Joseph Mackey, Neha Bansal, Andrew J. Martins, Boaz Palterer, Helen Matthews, Uma Mudunuri, Marshall Nambiar, Andrew J. Oler, Andre Rastegar, Smilee Samuel, Conrad Shyu, Varsha Waingankar, Sarah Weber, Sandhya Xirasagar, Yazmín Espinosa, Camila Astudillo, Cecilia Piñera, Ricardo González, Maria De Filippo, Martina Votto, Lorenza Montagna, 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,

SARS-CoV-2 and COVID-19 Research

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.