scholarly journals Unique transcriptional changes in coagulation cascade genes in SARS-CoV-2-infected lung epithelial cells: A potential factor in COVID-19 coagulopathies

2020 ◽  
Author(s):  
Ethan S. FitzGerald ◽  
Amanda M. Jamieson
Keyword(s):  
Epithelial Cells ◽  
Blood Coagulation ◽  
Influenza A ◽  
Coagulation Cascade ◽  
Data Sets ◽  
List Type ◽  
Plasminogen Activation ◽  
Plasminogen Activation System ◽  
Global Pandemic ◽  
Lung Epithelial

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (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. While there are many theories for the cause of this pathology, including hyper inflammation and excess tissue damage, the cellular and molecular underpinnings are not yet clear. By analyzing transcriptomic data sets from experimental and clinical research teams, we determined that changes in the gene expression of genes important in the extrinsic coagulation cascade in the lung epithelium may be important triggers for COVID-19 coagulopathy. This regulation of the extrinsic blood coagulation cascade is not seen with influenza A virus (IAV)-infected NHBEs suggesting that the lung epithelial derived coagulopathies are specific to SARS-Cov-2 infection. This study is the first to identify potential lung epithelial cell derived factors contributing to COVID-19 associated coagulopathy.GRAPHICAL ABSTRACTAUTHOR SUMMARYWhy was this study done?Severe acute respiratory syndrome coronavirus 2 (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. Understanding the molecular basis of dysregulated blood coagulation during SARS-CoV-2 infection may help promote new therapeutic strategies to mitigate these complications in COVID-19 patients.What did the researchers do and find?We analyzed three publicly available RNA sequencing datasets to identify possible molecular etiologies of COVID-19 associated coagulopathies. These data sets include sequencing libraries from clinically isolated samples of bronchoalveolar lavage fluid (BALF) and peripheral blood mononuclear cells (PBMCs) from SARS-CoV-2 positive patients and healthy controls. We also analyzed a publicly available RNA sequencing dataset derived from in vitro SARS-CoV-2 infected primary normal human bronchial epithelial (NHBE) cells and mock infected samples.Pathway analysis of both NHBE and BALF differential gene expression gene sets. We found that SARS-CoV-2 infection induces the activation of the extrinsic blood coagulation cascade and suppression of the plasminogen activation system in both NHBEs and cells isolated from the BALF. PBMCs did not differentially express genes regulating blood coagulation.Comparison with influenza A virus (IAV)-infected NHBEs revealed that the regulation of the extrinsic blood coagulation cascade is unique to SARS-CoV-2, and not seen with IAV infection.What do these findings mean?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.The gene transcription pattern in SARS-CoV-2 infected epithelial cells is distinct from IAV infected epithelial cells with regards to the regulation of blood coagulation.

Factors Involved In the Plasminogen Activation System in Human Breast Tumours

1994 ◽  
Vol 71 (05) ◽  
pp. 684-691 ◽  
Author(s):  
László Damjanovich ◽  
Csaba Turzó ◽  
Róza Ádány
Keyword(s):  
Epithelial Cells ◽  
Connective Tissue ◽  
Plasminogen Activators ◽  
Breast Tumour ◽  
Plasminogen Activation ◽  
Malignant Tumours ◽  
Plasminogen Activation System ◽  
Activation System ◽  
Malignant Breast ◽  
Pai 1

SummaryThe plasminogen activation system is a delicately balanced assembly of enzymes which seems to have primary influence on tumour progression. The conversion of plasminogen into serine protease plasmin with fibrinolytic activity depends on the actual balance between plasminogen activators (urokinase type; u-PA and tissue type; t-PA) and their inhibitors (type 1 and 2 plasminogen activator inhibitors; PAI-1 and PAI-2). The purpose of this study was to determine the exact histological localization of all the major factors involved in plasminogen activation, and activation inhibition (plasmin system) in benign and malignant breast tumour samples. Our results show that factors of the plasmin system are present both in benign and malignant tumours. Cancer cells strongly labelled for both u-PA and t-PA, but epithelial cells of fibroadenoma samples were also stained for plasminogen activators at least as intensively as tumour cells in cancerous tissues. In fibroadenomas, all the epithelial cells were labelled for PAM. Staining became sporadic in malignant tumours, cells located at the periphery of tumour cell clusters regularly did not show reaction for PAI-1. In the benign tumour samples the perialveolar connective tissue stroma contained a lot of PAI-1 positive cells, showing characteristics of fibroblasts; but their number was strongly decreased in the stroma of malignant tumours. These findings indicate that the higher level of u-PA antigen, detected in malignant breast tumour samples by biochemical techniques, does not necessarily indicate increased u-PA production by tumour cells but it might be owing to the increased number of cells producing u-PA as well. In malignant tumours PAI-1 seems to be decreased in the frontage of malignant cell invasion; i.e. malignant cells at the host/tumour interface do not express PAI-1 in morphologically detectable quantity and in the peritumoural connective tissue the number of fibroblasts containing PAI-1 is also decreased.

MC1568 inhibits HDAC6/8 activity and influenza A virus replication in lung epithelial cells: role of Hsp90 acetylation

2016 ◽  
Vol 8 (17) ◽  
pp. 2017-2031 ◽  
Author(s):  
Simona Panella ◽  
Maria Elena Marcocci ◽  
Ignacio Celestino ◽  
Sergio Valente ◽  
Clemens Zwergel ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Influenza A Virus ◽  
Virus Replication ◽  
Influenza A ◽  
Lung Epithelial Cells ◽  
Lung Epithelial

scholarly journals The NS1 Protein of Influenza A Virus Blocks RIG-I-Mediated Activation of the Noncanonical NF-κB Pathway and p52/RelB-Dependent Gene Expression in Lung Epithelial Cells

2012 ◽  
Vol 86 (18) ◽  
pp. 10211-10217 ◽  
Author(s):  
Andrea Rückle ◽  
Emanuel Haasbach ◽  
Ilkka Julkunen ◽  
Oliver Planz ◽  
Christina Ehrhardt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Influenza A Virus ◽  
Influenza A ◽  
Target Gene ◽  
Lung Epithelial Cells ◽  
Ns1 Protein ◽  
Antiviral Immune Response ◽  
Lung Epithelial ◽  
Infected Cells

Influenza A virus (IAV) infection of epithelial cells activates NF-κB transcription factors via the canonical NF-κB signaling pathway, which modulates both the antiviral immune response and viral replication. Since almost nothing is known so far about a function of noncanonical NF-κB signaling after IAV infection, we tested infected cells for activation of p52 and RelB. We show that the viral NS1 protein strongly inhibits RIG-I-mediated noncanonical NF-κB activation and expression of the noncanonical target gene CCL19.

scholarly journals Influenza A Virus Infection Induces Apical Redistribution of Na+, K+-ATPase in Lung Epithelial Cells In Vitro and In Vivo

2019 ◽  
Vol 61 (3) ◽  
pp. 395-398
Author(s):  
Christin Peteranderl ◽  
Irina Kuznetsova ◽  
Jessica Schulze ◽  
Martin Hardt ◽  
Emilia Lecuona ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Influenza A ◽  
Lung Epithelial Cells ◽  
Lung Epithelial ◽  
Influenza A Virus Infection

scholarly journals Novel miniature CRISPR–Cas13 systems from uncultivated microbes effective in degrading SARS-CoV-2 sequences and influenza viruses

2020 ◽  
Author(s):  
Chunlong Xu ◽  
Yingsi Zhou ◽  
Qingquan Xiao ◽  
Bingbing He ◽  
Guannan Geng ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Influenza A ◽  
Influenza Viruses ◽  
Data Sets ◽  
Metagenomic Sequence ◽  
Base Editing ◽  
Defense Systems ◽  
Mammalian Cell Lines ◽  
Global Pandemic ◽  
Single Effector

Abstract Recently emerging SARS-CoV-2 virus has caused a global pandemic, with millions of infections and over 200, 000 deaths1. However, development of effective anti-coronavirus treatments has lagged behind. Competitive co-evolution between microbes and viruses has led to the diversification of microbe’s CRISPR/Cas defense systems against infectious viruses2,3. Among class-2 single effector systems, Cas13 is effective in combating RNA phages4. Previous studies have discovered novel Cas9 and Cas12 systems from metagenomic sequence of natural microbes5-7. Here we report the identification of two additional compact Cas13 families from natural microbes that are effective in degrading RNA viruses in mammalian cells. Using metagenomic terabase data sets, we searched for previously uncharacterized Cas13 genes proximal to the CRISPR array with a customized computational pipeline, and identified two most compact families (775 to 803 amino acids) of CRISPR-Cas ribonucleases, named hereafter as CRISPR/Cas type VI-E and VI-F. Out of seven Cas13 proteins, we found that Cas13e.1 was the smallest and could be engineered for efficient RNA interference and base editing in cultured mammalian cell lines. Moreover, Cas13e.1 has a high activity for degrading SARS-CoV-2 sequences and the genome of live influenza A virus (IAV). Together with a minimal pool of 10 crRNAs, Cas13e.1 could target over 99% of all known 3,137 coronavirus genomes for achieving antiviral defense. Overall, our results demonstrated there exist untapped bacterial defense systems in natural microbes that can function efficiently in mammalian cells, thus potentially useful for preventing viral infection in humans such as COVID-19.

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