Τίτλος:
Expression profiling meta-analysis of ACE2 and TMPRSS2, the putative anti-inflammatory receptor and priming protease of SARS-CoV-2 in human cells, and identification of putative modulators
Περίληψη:
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in hundreds of thousands of deaths worldwide. While the majority of people with COVID-19 won't require hospitalization, those who do may experience severe life-threatening complications, including acute respiratory distress syndrome. SARS-CoV-2 infects human cells by binding to the cellular surface protein angiotensin-converting enzyme 2 (ACE2); in addition, the cellular transmembrane serine protease 2 (TMPRSS2) is needed for priming of the spike (S) protein of the virus. Virus entry may also depend on the activity of the endosomal/lysosomal cysteine proteases cathepsin B, L (CTSB, CTSL) although their activity is likely dispensable. Given that the uncertainty of how COVID-19 kills, hampers doctors' ability to choose treatments the need for a deep understanding of COVID-19 biology is urgent. Herein, we performed an expression profiling meta-analysis of ACE2, TMPRSS2 and CTSB/L genes (and proteins) in public repository databases and found that all are widely expressed in human tissues; also, the ACE2 and TMPRSS2 genes tend to be co-regulated. The ACE2 and TMPRSS genes expression is (among others) suppressed by TNF, and is induced by pro-inflammatory conditions including obesity, Barrett's esophagus, stomach infection by helicobacter pylori, diabetes, autoimmune diseases and oxidized LDL; by exercise, as well as by growth factors, viruses' infections, cigarette smoke, interferons and androgens. Regarding currently investigated therapies interferon-beta induced ACE2 gene expression in bronchial epithelial cells, while chloroquine tends to upregulate CTSB/L genes. Finally, we analyzed KEGG pathways modulated by ACE2, TMPRSS2 and CTSB/L and probed DrugBank for drugs that target modules of the affected pathways. Our data indicate possible novel high-risk groups for COVID-19; provide a rich resource for future investigations of its pathogenesis and highlight the therapeutic challenges we face. © 2020 The Author(s)
Συγγραφείς:
Gkogkou, E.
Barnasas, G.
Vougas, K.
Trougakos, I.P.
Λέξεις-κλειδιά:
angiotensin converting enzyme 2; cathepsin B; serine proteinase; transmembrane serine protease 2; unclassified drug; viral protein; angiotensin converting enzyme 2; cathepsin; dipeptidyl carboxypeptidase; dipeptidyl carboxypeptidase inhibitor; serine proteinase; serine proteinase inhibitor; TMPRSS2 protein, human, ACE2 gene; Article; autoimmune disease; Barrett esophagus; controlled study; coronavirus disease 2019; diabetes mellitus; epithelium cell; gene; gene expression; gene expression profiling; genetic database; Helicobacter infection; human; human cell; obesity; pathogenesis; priority journal; protein binding; SARS coronavirus; smoking; TMPRSS2 gene; virus entry; Betacoronavirus; drug effect; gene expression profiling; genetics; intestine mucosa; kidney; meta analysis; metabolism; physiology; respiratory mucosa, Angiotensin-Converting Enzyme Inhibitors; Betacoronavirus; Cathepsins; Gene Expression Profiling; Humans; Intestinal Mucosa; Kidney; Peptidyl-Dipeptidase A; Respiratory Mucosa; Serine Endopeptidases; Serine Proteinase Inhibitors; Virus Internalization
