@article{aa2d2fc335d5486fb98253d475e0ccab,
title = "Longitudinal Multi-omics Analyses Identify Responses of Megakaryocytes, Erythroid Cells, and Plasmablasts as Hallmarks of Severe COVID-19",
abstract = "Temporal resolution of cellular features associated with a severe COVID-19 disease trajectory is needed for understanding skewed immune responses and defining predictors of outcome. Here, we performed a longitudinal multi-omics study using a two-center cohort of 14 patients. We analyzed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. Validation was performed in two independent cohorts of COVID-19 patients. Severe COVID-19 was characterized by an increase of proliferating, metabolically hyperactive plasmablasts. Coinciding with critical illness, we also identified an expansion of interferon-activated circulating megakaryocytes and increased erythropoiesis with features of hypoxic signaling. Megakaryocyte- and erythroid-cell-derived co-expression modules were predictive of fatal disease outcome. The study demonstrates broad cellular effects of SARS-CoV-2 infection beyond adaptive immune cells and provides an entry point toward developing biomarkers and targeted treatments of patients with COVID-19.",
keywords = "COVID-19, RNA-seq, acute respiratory distress, blood, disease trajectory, immune response, infectious disease, methylation, scRNA-seq, virus",
author = "{HCA Lung Biological Network} and {the Deutsche COVID-19 Omics Initiative (DeCOI)} and Bernardes, {Joana P.} and Neha Mishra and Florian Tran and Thomas Bahmer and Lena Best and Blase, {Johanna I.} and Dora Bordoni and Jeanette Franzenburg and Ulf Geisen and Jonathan Josephs-Spaulding and Philipp K{\"o}hler and Axel K{\"u}nstner and Elisa Rosati and Aschenbrenner, {Anna C.} and Petra Bacher and Nathan Baran and Teide Boysen and Burkhard Brandt and Niklas Bruse and Jonathan D{\"o}rr and Andreas Dr{\"a}ger and Gunnar Elke and David Ellinghaus and Julia Fischer and Michael Forster and Andre Franke and S{\"o}ren Franzenburg and Norbert Frey and Anette Friedrichs and Janina Fu{\ss} and Andreas Gl{\"u}ck and Jacob Hamm and Finn Hinrichsen and Hoeppner, {Marc P.} and Simon Imm and Ralf Junker and Sina Kaiser and Kan, {Ying H.} and Rainer Knoll and Christoph Lange and Georg Laue and Clemens Lier and Matthias Lindner and Georgios Marinos and Robert Markewitz and Jacob Nattermann and Rainer Noth and Peter Pickkers and Rabe, {Klaus F.} and Douglas Shepherd",
note = "Funding Information: We thank K. Greve, M. Rohm, M. Hansen, S. Kock, D. Oelsner, S. Baumgarten, M. Reffelmann, M. Schlapkohl, N. Braun, T. Wesse, M. Basso, Y. Dolschanskaya, X. Yi, C. Lancken, and M. Vollstedt for perfect technical assistance. This work was supported by the German Research Foundation (DFG) CCGA Nr. 07495230 , a COVID-response grant of the state SH , ExC 2167 Precision Medicine in Chronic Inflammation ( RTF-VI ), the research group miTARGET and the CRC1182 C2 project to P.R.; the IMI2 Project 3TR to P.R. and S.S.; INST 37/1049-1 , INST 216/981-1 , INST 257/605-1 , INST 269/768-1 , INST 217/988-1 , INST 217/577-1 , and EXC2151/1 ( 390873048 ) to J.L.S.; SFB TR57 and SPP1937 to J.N.; Helmholtz-Gemeinschaft Deutscher Forschungszentren, Germany ( sparse2big ) to J.L.S.; EU projects SYSCID ( 733100 ) to P.R. and J.L.S.; the DZIF, Germany ( TTU 04.816 and 04.817 ) to J.N.; and the Hector Foundation ) ( M89 ) to J.N. A.D. acknowledges support by the DFG ( EXC 2124-390838134 Controlling Microbes to Fight Infections) and the German Center for Infection Research (DZIF grant N° 8020708703). C.K. acknowledges support by the DFG through EXC 2167 , RTF-VIII , and the CRC 1182 . This publication is part of the Human Cell Atlas ( www.humancellatlas.org/publications ). We are indebted to the patients, their families, and the hospital staff for support, without whom this study would not have been possible. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = dec,
day = "15",
doi = "10.1016/j.immuni.2020.11.017",
language = "English (US)",
volume = "53",
pages = "1296--1314.e9",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "6",
}