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Key Event Title
Increased viral entry and gene expression
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|ACE2 binding to viral S protein, Acute respiratory distress||KeyEvent||Evgeniia Kazymova (send email)||Open for comment. Do not cite|
|SARS-CoV2 to thrombosis||MolecularInitiatingEvent||Arthur Author (send email)||Under development: Not open for comment. Do not cite|
|SARS-CoV2 to hyperinflammation||MolecularInitiatingEvent||Hasmik Yepiskoposyan (send email)||Under development: Not open for comment. Do not cite|
|Homo sapiens||Homo sapiens||High||NCBI|
|All life stages||High|
Key Event Description
Coronavirus, which is a nanoparticle, is sphere-shaped and its diameter is 80-120 nm in average, where it sometimes ranges from 50 nm to 200 nm [Masters PS. (2006)]. Spike protein (S protein), so-called peplomer, on the surface of the particle binds to the receptor on the host cellular membrane, then internalized inside the cells. Viral RNA (plus strand) in the viral particles is replicated and translated into the viral structure protein in the host cells, which is followed by replication of new viral particles [Weiss SR, Navas-Martin S. (2005) ]. Coronavirus is recognized by the binding of S protein on the viral surface and angiotensin I converting enzyme 2 (ACE2) receptor on the cellular membrane, then internalized into the cell via processing of S protein by transmembrane serine protease 2 (TMPRSS2) protease [Hoffmann M, et al. (2020)]. The inhibition of this internalization of the viral particle would theoretically prevent the viral infection and replication T[anabe S. (2020)].
How It Is Measured or Detected
SARS-CoV entry can be determined by quantitative RT-PCR specific to the subgenomic mRNA of the N transcript, following the infection of the 293T-hACE2 cells with SARS-CoV [Glowacka I, et al. (2011)].
For analyzing cell entry of S protein of SARS-CoV-2, vesicular stomatitis virus (VSV) particles expressing eGFP and firefly luciferase bearing SARS-2-S are cultured with cell lines, followed by determining luciferase activity in cell lysates [Hoffmann M, et al. (2020)].
Domain of Applicability
ACE 2 is highly expressed in gastrointestinal system such as small intestine and duodenum, as well as oral and nasal mucosa, lung, kidney and brain [6-8].
Evidence for Perturbation by Stressor
Overview for Molecular Initiating Event
Masters PS. (2006) The molecular biology of coronaviruses. Adv Virus Res. 66:193-292.
Weiss SR, Navas-Martin S. (2005) Coronavirus pathogenesis and the emerging pathogen severe acute
respiratory syndrome coronavirus. Microbiol Mol Biol Rev. 69(4):635-64.
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, et al. (2020).SARS-CoV-2 Cell Entry
Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 181(2):271-
Tanabe S. (2020) Cellular Internalization and RNA Regulation of RNA Virus. Adv Clin Med Res. 1(1):1-3.
Glowacka I, Bertram S, Müller MA, Allen P, Soilleux E, Pfefferle S, et al. Evidence that TMPRSS2 Activates the Severe Acute Respiratory Syndrome Coronavirus Spike Protein for Membrane Fusion and Reduces Viral Control by the Humoral Immune Response. Journal of Virology. 2011;85(9):4122.
Fagerberg L, Hallström BM, Oksvold P, Kampf C. Djureinovic D, et al. (2014) Analysis of the human tissue- specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. 13(2):397-406.
Farmer D, Gilbert M, Borman R, Clark KL. (2002) Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme. FEBS Lett. 532(1-2):107-110.
Xu H, Zhong L, Deng J, Peng J, Dan H, et al. (2020) High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Science. 12(1):8.