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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.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been led to a pandemic emergency. So far, different pathological pathways for SARS-CoV-2 infection have been introduced in which the excess release of pro-inflammatory cytokines (such as interleukin 1 β [IL-1β], IL-6, and tumor necrosis factor α [TNFα]) has earned most of the attentions. However, recent studies have identified new pathways with at least the same level of importance as cytokine storm in which endothelial cell (EC) dysfunction is one of them. In COVID-19, two main pathologic phenomena have been seen as a result of EC dysfunction: hyper-coagulation state and pathologic angiogenesis. The EC dysfunction-induced hypercoagulation state seems to be caused by alteration in the levels of different factors such as plasminogen activator inhibitor 1 (PAI-1), von Willebrand factor (vWF) antigen, soluble thrombomodulin, and tissue factor pathway inhibitor (TFPI). As data have shown, these thromboembolic events are associated with severity of disease severity or even death in COVID-19 patients. Other than thromboembolic events, pathologic angiogenesis is among the recent findings. Furthermore, over-expression/higher levels of different proangiogenic factors such as vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1 α (HIF-1α), IL-6, TNF receptor super family 1A and 12, and angiotensin-converting enzyme 2 (ACE2) have been found in the lung biopsies/sera of both survived and non-survived COVID-19 patients. Also, there are some hypotheses regarding the role of nitric oxide in EC dysfunction and acute respiratory distress syndrome (ARDS) in SARS-CoV-2 infection. It has been demonstrated that different pathways involved in inflammation are generally common with EC dysfunction and angiogenesis. Altogether, considering the common possible upstream pathways in cytokine storm, pathologic angiogenesis, and EC dysfunction, it seems that targeting these molecules (such as nuclear factor κB) could be more effective in the management of patients with COVID-19., Graphical abstract Unlabelled Image