Summary
COVID-19 has caused over 1 million deaths globally, yet the cellular mechanisms underlying severe disease remain poorly understood. By analyzing several thousand plasma proteins in 306 COVID-19 patients and 78 symptomatic controls over serial timepoints using two complementary approaches, we uncover COVID-19 host immune and non-immune proteins not previously linked to this disease. Integration of plasma proteomics with nine published scRNAseq datasets shows that SARS-CoV-2 infection upregulates monocyte/macrophage, plasmablast, and T cell effector proteins. By comparing patients who died to severely ill patients who survived, we identify dynamic immunomodulatory and tissue-associated proteins associated with survival, providing insights into which host responses are beneficial and which are detrimental to survival. We identify intracellular death signatures from specific tissues and cell types, and by associating these with angiotensin converting enzyme 2 (ACE2) expression, we map tissue damage associated with severe disease and propose which damage results from direct viral infection rather than from indirect effects of illness. We find that disease severity in lung tissue is driven by myeloid cell phenotypes and cell-cell interactions with lung epithelial cells and T cells. Based on these results, we propose a model of immune and epithelial cell interactions that drive cell-type specific and tissue-specific damage in severe COVID-19.
Competing Interest Statement
Jamey R. Guess and Ida Grundberg are employees of Olink Proteomics, Inc. and Lori Jennings, an employee and stockholder of Novartis, performed the SomaLogic assay. No other authors have competing interests.
Footnotes
↵* Denotes co-first authors, listed in alphabetical order.
↵† Denotes co-senior authors.
The acknowledgement section of the manuscript has been updated to reflect: 1) N.H. was funded by a gift from Arthur, Sandra, and Sarah Irving for the David P. Ryan, MD Endowed Chair in Cancer Research. 2) Remove last sentence "We are also very grateful for the generous contributions of Olink Proteomics Inc. for providing in-kind all proteomics assays presented in this work, and to Novartis for sponsoring the Somalogic assay presented in this work, without either of which our findings would not have been possible. 3) Add 'We are also very grateful for the generous contributions of Olink Proteomics Inc. and Novartis (in collaboration with SomaLogic, Inc.) for providing in-kind all proteomics assays presented in this work, without which our findings would not have been possible.