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

Bernardes et al.▾ Bernardes, J.P.*, Mishra, N.*, Tran, F.*, Bahmer, T.#, Best, L.#, Blase, J.I.#, Bordoni, D.#, Franzenburg, J.#, Geisen, U.#, Josephs-Spaulding, J.#, Köhler, P.#, Künstner, A.#, Rosati, E.#, Aschenbrenner, A.C., Bacher, P., Baran, N., Boysen, T., Brandt, B., Bruse, N., Dörr, J., Dräger, A., Elke, G., Ellinghaus, D., Fischer, J., Forster, M., Franke, A., Franzenburg, S., Frey, N., Friedrichs, A., Fuß, J., Glück, A., Hamm, J., Hinrichsen, F., Hoeppner, M.P., Imm, S., Junker, R., Kaiser, S., Kan, Y.H., Knoll, R., Lange, C., Laue, G., Lier, C., Lindner, M., Marinos, G., Markewitz, R., Nattermann, J., Noth, R., Pickkers, P., Rabe, K.F., Renz, A., Röcken, C., Rupp, J., Schaffarzyk, A., Scheffold, A., Schulte-Schrepping, J., Schunk, D., Skowasch, D., Ulas, T., Wandinger, K.-P., Wittig, M., Zimmermann, J., Busch, H.$, Hoyer, B.F.$, Kaleta, C.$, Heyckendorf, J.$, Kox, M.$, Rybniker, J.$, Schreiber, S.$, Schultze, J.L.$, Rosenstiel, P.$, HCA Lung Biological Network, Deutsche COVID-19 Omics Initiative (DeCOI)

Immunity , Volume 53

March, 2023

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.