Longitudinal multi-omics analysis identifies responses of megakaryocytes, erythroid cells and plasmablasts as hallmarks of severe COVID-19 trajectories
Authors: Bernardes Joana P. , Mishra Neha , Tran Florian , Bahmer Thomas , Best Lena , Blase Johanna I. , Bordoni Dora , Franzenburg Jeanette , Geisen Ulf , Josephs-Spaulding Jonathan , Köhler Philipp , Künstner Axel , Rosati Elisa , Aschenbrenner Anna C. , Bacher Petra , Baran Nathan , Boysen Teide , Brandt Burkhard , Bruse Niklas , Dörr Jonathan , Dräger Andreas , Elke Gunnar , Ellinghaus David , Fischer Julia , Forster Michael , Franke Andre , Franzenburg Sören , Frey Norbert , Friedrichs Anette , Fuß Janina , Glück Andreas , Hamm Jacob , Hinrichsen Finn , Hoeppner Marc P. , Imm Simon , Junker Ralf , Kaiser Sina , Kan Ying H. , Knoll Rainer , Lange Christoph , Laue Georg , Lier Clemens , Lindner Matthias , Marinos Georgios , Markewitz Robert , Nattermann Jacob , Noth Rainer , Pickkers Peter , Rabe Klaus F. , Renz Alina , Röcken Christoph , Rupp Jan , Schaffarzyk Annika , Scheffold Alexander , Schulte-Schrepping Jonas , Schunck Domagoj , Skowasch Dirk , Ulas Thomas , Wandinger Klaus-Peter , Wittig Michael , Zimmermann Johannes , Busch Hauke , Hoyer Bimba , Kaleta Christoph , Heyckendorf Jan , Kox Matthijs , Rybniker Jan , Schreiber Stefan , Schultze Joachim , Rosenstiel Philip ,   HCA Lung Biological Network and the Deutsche COVID-19 Omics Initiative (DeCOI)
Published: September 2020

AbstractThe 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.