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

• Published in: Viruses Vol. 14; no. 12; p. 2753
• Main Authors: Silva, Bruna Rafaela Santos, Jara, Carlos Poblete, Sidarta-Oliveira, Davi, Velloso, Licio A., Velander, William H., Araújo, Eliana P.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.12.2022; MDPI
• Subjects: ACE2; Activated protein C; Analysis; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - genetics; Angiotensin-Converting Enzyme 2 - metabolism; antigen-presenting cell; blood coagulation disorders; Blood vessels; C gene; Catalysis; Clustering; Coagulation; computational biology; Coronaviruses; COVID-19; COVID-19 - genetics; COVID-19 infection; Datasets; Down-Regulation; endothelial cells; Epithelium; Gene expression; genes; Hepatocytes; Humans; Immune response; immune system; Inflammation; Leukocytes (mononuclear); Leukocytes, Mononuclear - metabolism; Liver; Mann-Whitney U test; Medical research; Neighborhoods; nose; Peptidyl-Dipeptidase A - metabolism; Peripheral blood mononuclear cells; Protein C; Protein C - genetics; Protein C - metabolism; protein-protein interactions; Proteins; SARS-CoV-2; SARS-CoV-2 - genetics; sequence analysis; Thrombophilia - genetics; Transcriptome; Transcriptomics; Brazil; blood coagulation disorders; computational biology; SARS-CoV-2; endothelial cells; antigen-presenting cell
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v14122753

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.