4.6 Article

Downregulation of the Protein C Signaling System Is Associated with COVID-19 Hypercoagulability-A Single-Cell Transcriptomics Analysis

Journal

VIRUSES-BASEL
Volume 14, Issue 12, Pages -

Publisher

MDPI
DOI: 10.3390/v14122753

Keywords

antigen-presenting cell; computational biology; blood coagulation disorders; endothelial cells; SARS-CoV-2

Categories

Funding

  1. Sao Paulo Research Foundation
  2. Coordination for the Improvement of Higher Education Personnel-Brazil (CAPES) [001]
  3. Nebraska DHHS Stem Cell Grant 2019
  4. CEPID-FAPESP-OCRC-Obesity and Comorbidities Research Center, Brazil [2013/07607-8]

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This study found changes in the expression of the protein C signaling network in patients with COVID-19, including downregulation of protein C and its downstream cascade components. Transcripts encoding proteins at the interface between coagulation and the immune system were upregulated in the liver and peripheral blood cells, while ciliated cells in the nasal epithelium expressed transcripts encoding both ACE2 and proteins related to the coagulation and immune system interface.
Because of the interface between coagulation and the immune response, it is expected that COVID-19-associated coagulopathy occurs via activated protein C signaling. The objective was to explore putative changes in the expression of the protein C signaling network in the liver, peripheral blood mononuclear cells, and nasal epithelium of patients with COVID-19. Single-cell RNA-sequencing data from patients with COVID-19 and healthy subjects were obtained from the COVID-19 Cell Atlas database. A functional protein-protein interaction network was constructed for the protein C gene. Patients with COVID-19 showed downregulation of protein C and components of the downstream protein C signaling cascade. The percentage of hepatocytes expressing protein C was lower. Part of the liver cell clusters expressing protein C presented increased expression of ACE2. In PBMC, there was increased ACE2, inflammatory, and pro-coagulation transcripts. In the nasal epithelium, PROC, ACE2, and PROS1 were expressed by the ciliated cell cluster, revealing co-expression of ACE-2 with transcripts encoding proteins belonging to the coagulation and immune system interface. Finally, there was upregulation of coagulation factor 3 transcript in the liver and PBMC. Protein C could play a mechanistic role in the hypercoagulability syndrome affecting patients with severe COVID-19.

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