Title
Lung Epithelial Cell Transcriptional Regulation as a Factor in COVID-19 Associated Coagulopathies
UMMS Affiliation
Division of Infectious Disease and Immunology, Department of Medicine
Publication Date
2021-03-19
Document Type
Article Postprint
Disciplines
Cell Biology | Hemic and Lymphatic Diseases | Immunology of Infectious Disease | Immunopathology | Infectious Disease | Microbiology | Molecular Biology | Pathology | Respiratory Tract Diseases | Virus Diseases
Abstract
SARS-CoV-2 has rapidly become a global pandemic. In addition to the acute pulmonary symptoms of COVID-19 (the disease associated with SARS-CoV-2 infection), pulmonary and distal coagulopathies have caused morbidity and mortality in many patients. Currently, the molecular pathogenesis underlying COVID-19 associated coagulopathies are unknown. Identifying the molecular basis of how SARS-CoV-2 drives coagulation is essential to mitigating short and long term thrombotic risks of sick and recovered COVID-19 patients. We aimed to perform coagulation focused transcriptome analysis of in vitro infected primary respiratory epithelial cells, patient derived bronchial alveolar lavage (BALF) cells, and circulating immune cells during SARS-CoV-2 infection. Our objective was to identify transcription mediated signaling networks driving coagulopathies associated with COVID-19. We analyzed recently published experimentally and clinically derived bulk or single cell RNA sequencing datasets of SARS-CoV-2 infection to identify changes in transcriptional regulation of blood coagulation. We also confirmed that the transcriptional expression of a key coagulation regulator was recapitulated at the protein level. We specifically focused our analysis on lung tissue expressed genes regulating the extrinsic coagulation cascade and the plasminogen activation system. Analyzing transcriptomic data of in vitro infected normal human bronchial epithelial (NHBE) cells and patient derived BALF samples revealed that SARS-CoV-2 infection induces the extrinsic blood coagulation cascade and suppresses the plasminogen activation system. We also performed in vitro SARS-CoV-2 infection experiments on primary human lung epithelial cells to confirm that transcriptional upregulation of Tissue Factor, the extrinsic coagulation cascade master regulator, manifested at the protein level. Further, infection of NHBEs with influenza A virus (IAV) did not drive key regulators of blood coagulation in a similar manner as SARS-CoV-2. Additionally, peripheral blood mononuclear cells (PBMCs) did not differentially express genes regulating the extrinsic coagulation cascade or plasminogen activation system during SARS-CoV-2 infection, suggesting that they are not directly inducing coagulopathy through these pathways. The hyper-activation of the extrinsic blood coagulation cascade and the suppression of the plasminogen activation system in SARS-CoV-2 infected epithelial cells may drive diverse coagulopathies in the lung and distal organ systems. Understanding how hosts drive such transcriptional changes with SARS-CoV-2 infection may enable the design of host-directed therapeutic strategies to treat COVID-19 and other coronaviruses inducing hyper-coagulation.
Keywords
SARS-CoV-2, COVID-19, pulmonary and distal coagulopathies, molecular pathogenesis, lung epithelial cells
Rights and Permissions
This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
DOI of Published Version
10.1165/rcmb.2020-0453OC
Source
FitzGerald ES, Chen Y, Fitzgerald KA, Jamieson AM. Lung Epithelial Cell Transcriptional Regulation as a Factor in COVID-19 Associated Coagulopathies. Am J Respir Cell Mol Biol. 2021 Mar 19. doi: 10.1165/rcmb.2020-0453OC. Epub ahead of print. PMID: 33740387. Link to article on publisher's site
Journal/Book/Conference Title
American journal of respiratory cell and molecular biology
Related Resources
PubMed ID
33740387
Repository Citation
FitzGerald ES, Chen Y, Fitzgerald KA, Jamieson AM. (2021). Lung Epithelial Cell Transcriptional Regulation as a Factor in COVID-19 Associated Coagulopathies. COVID-19 Publications by UMass Chan Authors. https://doi.org/10.1165/rcmb.2020-0453OC. Retrieved from https://escholarship.umassmed.edu/covid19/185
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Included in
Cell Biology Commons, Hemic and Lymphatic Diseases Commons, Immunology of Infectious Disease Commons, Immunopathology Commons, Infectious Disease Commons, Microbiology Commons, Molecular Biology Commons, Pathology Commons, Respiratory Tract Diseases Commons, Virus Diseases Commons