Longitudinal multi-omics analysis identifies responses of megakaryocytes, erythroid cells and plasmablasts as hallmarks of severe COVID-19 trajectories
Authors
Joana Bernardes, Neha Mishra, Florian Tran, Thomas Bahmer, Lena Best, Johanna Blase, Dora Bordoni, Jeanette Franzenburg, Ulf Geisen, Jonathan Josephs-Spaulding, Philipp Köhler, Axel Künstner, Elisa Rosati, Anna 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 Hoeppner, Simon Imm, Ralf Junker, Sina Kaiser, Ying Kan, Rainer Knoll, Christoph Lange, Georg Laue, Clemens Lier, Matthias Lindner, Georgios Marinos, Robert Markewitz, Jacob Nattermann, Rainer Noth, Peter Pickkers, Klaus Rabe, Alina Renz, Christoph Röcken, Jan Rupp, Annika Schaffarzyk, Alexander Scheffold, Jonas Schulte-Schrepping, Domagoj Schunck, Dirk Skowasch, Thomas Ulas, Klaus-Peter Wandinger, Michael Wittig, Johannes Zimmermann, Hauke Busch, Bimba Hoyer, Christoph Kaleta, Jan Heyckendorf, Matthijs Kox, Jan Rybniker, Stefan Schreiber, Joachim Schultze, Philip Rosenstiel
Year of publication
2020Journal
UKNVolume
-Issue
-Abstract
The pandemic spread of the potentially life-threatening disease COVID-19 requires a thorough understanding of the longitudinal dynamics of host responses. Temporal resolution of cellular features associated with a severe disease trajectory will be a pre-requisite for finding disease outcome predictors. Here, we performed a longitudinal multi-omics study using a two-centre German cohort of 13 patients (from Cologne and Kiel, cohort 1). We analysed 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. The results from single-cell and bulk transcriptome analyses were validated in two independent cohorts of COVID-19 patients from Bonn (18 patients, cohort 2) and Nijmegen (40 patients, cohort 3), respectively. We observed an increase of proliferating, activated plasmablasts in severe COVID-19, and show a distinct expression pattern related to a hyperactive cellular metabolism of these cells. We further identified a notable expansion of type I IFN-activated circulating megakaryocytes and their progenitors, indicative of emergency megakaryopoiesis, which was confirmed in cohort 2. These changes were accompanied by increased erythropoiesis in the critical phase of the disease with features of hypoxic signalling. Finally, projecting megakaryocyte- and erythroid cell-derived co-expression modules to longitudinal blood transcriptome samples from cohort 3 confirmed an association of early temporal changes of these features with fatal COVID-19 disease outcome. In sum, our longitudinal multi-omics study demonstrates distinct cellular and gene expression dynamics upon SARS-CoV-2 infection, which point to metabolic shifts of circulating immune cells, and reveals changes in megakaryocytes and increased erythropoiesis as important outcome indicators in severe COVID-19 patients.