Longitudinal Multi-omics Analyses Identify Responses of Megakaryocytes, Erythroid Cells, and Plasmablasts as Hallmarks of Severe COVID-19.

Joana P Bernardes, Neha Mishra, Florian Tran, Thomas Bahmer, Lena Best, Johanna I Blase, Dora Bordoni, Jeanette Franzenburg, Ulf Geisen, Jonathan Josephs-Spaulding, Philipp Köhler, Axel Künstner, Elisa Rosati, Anna C Aschenbrenner, Petra Bacher, Nathan Baran, Teide Boysen, Burkhard Brandt, Niklas Bruse, Jonathan Dörr, Andreas Dräger, Gunnar Elke, David Ellinghaus, Julia Fischer, Michael Forster, Andre Franke, Sören Franzenburg, Norbert Frey, Anette Friedrichs, Janina Fuß, Andreas Glück, Jacob Hamm, Finn Hinrichsen, Marc P Hoeppner, Simon Imm, Ralf Junker, Sina Kaiser, Ying H Kan, Rainer Knoll, Christoph Lange, Georg Laue, Clemens Lier, Matthias Lindner, Georgios Marinos, Robert Markewitz, Jacob Nattermann, Rainer Noth, Peter Pickkers, Klaus F Rabe, Alina Renz, Christoph Röcken, Jan Rupp, Annika Schaffarzyk, Alexander Scheffold, Jonas Schulte-Schrepping, Domagoj Schunk, Dirk Skowasch, Thomas Ulas, Klaus-Peter Wandinger, Michael Wittig, Johannes Zimmermann, Hauke Busch, Bimba F Hoyer, Christoph Kaleta, Jan Heyckendorf, Matthijs Kox, Jan Rybniker, Stefan Schreiber, Joachim L Schultze, Philip Rosenstiel
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Immunity (Cambridge, Mass.)
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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.