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Cytotoxic lymphocytes are dysregulated in multisystem inflammatory syndrome in children

By Noam D Beckmann, Phillip H. Comella, Esther Cheng, Lauren Lepow, Aviva G. Beckmann, Konstantinos Mouskas, Nicole W. Simons, Gabriel E. Hoffman, Nancy J. Francoeur, Diane Marie Del Valle, Gurpawan Kang, Emily Moya, Lillian Wilkins, Jessica Le Berichel, Christie Chang, Robert Marvin, Sharlene Calorossi, Alona Lansky, Laura Walker, Nancy Yi, Alex Yu, Matthew Harnett, Melody Eaton, Sandra Hatem, Hajra Jamal, Alara Akyatan, Alexandra Tabachnikova, Lora E. Liharska, Liam Cotter, Brian Fennessey, Akhil Vaid, Guillermo Barturen, Scott R. Tyler, Hardik Shah, Yinh-chih Wang, Shwetha Hara Sridhar, Juan Soto, Swaroop Bose, Kent Madrid, Ethan Ellis, Elyze Merzier, Konstantinos Vlachos, Nataly Fishman, Manying Tin, Melissa Smith, Hui Xie, Manishkumar Patel, Kimberly Argueta, Jocelyn Harris, Neha Karekar, Craig Batchelor, Jose Lacunza, Mahlet Yishak, Kevin Tuballes, Leisha Scott, Arvind Kumar, Suraj Jaladanki, Ryan Thompson, Evan Clark, Bojan Losic, The Mount Sinai COVID-19 Biobank Team, Jun Zhu, Wenhui Wang, Andrew Kasarskis, Benjamin S Glicksberg, Girish Nadkarni, Dusan Bogunovic, Cordelia Elaiho, Sandeep Gangadharan, George Ofori-Amanfo, Kasey Alesso-Carra, Kenan Onel, Karen M. Wilson, Carmen Argmann, Marta E. Alarc_n-Riquelme, Thomas U. Marron, Adeeb H Rahman, Seunghee Kim-Schulze, Sacha Gnjatic, Bruce D Gelb, Miriam Merad, Robert Sebra, Eric E. Schadt, Alexander William Charney

Posted 02 Sep 2020
medRxiv DOI: 10.1101/2020.08.29.20182899

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and multiple organ involvement in individuals under 21 years following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To identify genes, pathways and cell types driving MIS-C, we sequenced the blood transcriptomes of MIS-C cases, pediatric cases of coronavirus disease 2019, and healthy controls. We define a MIS-C transcriptional signature partially shared with the transcriptional response to SARS-CoV-2 infection and with the signature of Kawasaki disease, a clinically similar condition. By projecting the MIS-C signature onto a co-expression network, we identified disease gene modules and found genes downregulated in MIS-C clustered in a module enriched for the transcriptional signatures of exhausted CD8+ T-cells and CD56dimCD57+ NK cells. Bayesian network analyses revealed nine key regulators of this module, including TBX21, a central coordinator of exhausted CD8+ T-cell differentiation. Together, these findings suggest dysregulated cytotoxic lymphocyte response to SARS-Cov-2 infection in MIS-C.

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