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Meta-Analysis
. 2020 Sep:36:101615.
doi: 10.1016/j.redox.2020.101615. Epub 2020 Jun 24.

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

Eirini Gkogkou  1 , Grigoris Barnasas  1 , Konstantinos Vougas  2 , Ioannis P Trougakos  3
Affiliations
Meta-Analysis

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

Eirini Gkogkou et al. Redox Biol. 2020 Sep.

Abstract

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.

Keywords: ACE2; COVID-19; CTSB/L; Gene expression; SARS-CoV-2; TMPRSS2.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Illustration of the main components of the ACE/ANGII/AT1R and ACE2/ANG(1–7)/MASR axes along with the other molecular components reported to be involved in SARS-CoV-2 infection (e.g. TMPRSS2 or FURIN) in human cells. The pathway of SARS-CoV-2 endocytosis and replication in cells is also indicated. ❶ SARS-CoV-2 (extracellular or in circulation); ❷ binding to ACE2; ❸ TMPRSS2 priming; ❹ clathrin-mediated endocytosis (entry to early and acidic late -microtubule bound-endosomes); ❺, ❻ uncoating and viral proteins synthesis in free and endoplasmic reticulum (ER) attached ribosomes; ❼ vesicle-mediated exocytosis; ❽ MHC class II and MHC class I antigen (Ag) presentation by endocytic compartments and proteasome respectively; ❾ immune cells attraction and development of immunity or elimination of infected cells. The hemagglutinin-esterase dimmer component of SARS-CoV-2 is not shown. → induction, ┤inhibition.
Fig. 2
Fig. 2
Patterns of differentially expressed ACE2 (A1) and TMPRSS2 (B1) genes, along with expression levels in human tissues [ACE2, (A2); TMPRSS2, (B2)] in GEO and ArrayExpress deposited experiments. Dashed line in (B2) represents the mean TMPRSS2 gene expression in female tissues. See also Tables S1 and S2. Bars, ± SD. *, P < 0.05, **, P < 0.01.
Fig. 3
Fig. 3
Comparative ACE2, TMPRSS2, CTSB and CTSL genes (mRNA) expression and correlative co-expression analyses (B) at the shown tissues or cell types/lines (Protein Atlas data). See also, Table S3.
Fig. 4
Fig. 4
Differential regulation of ACE2, TMPRSS2, CTSB and CTSL genes following treatment in shown biological settings with IFN1-β (A), chloroquine (B) or hydroxychloroquine (C). Data from GEO and ArrayExpress. See also Tables S5–S7. Bars, ± SD. *, P < 0.05, **, P < 0.01.
Fig. 5
Fig. 5
Graphical illustration of ACE2, TMPRSS2, CTSB and CTSL proteins expression in various somatic tissues as per the Protein Atlas database (A) (see also, Fig. S3, Table S4). The distinct, i.e. early (B) and acute (C) phases of SARS-CoV-2 infection in lung alveoli are also shown. The major cell types, local tissue alterations and inflammatory cytokines that relate to the disease in the lung are indicated. ❶ Sites of SARS-CoV-2 entry in the body; ❷ likely inflammatory responses at the gastrointestinal tract; ❸ early phases of virus entry to the lung – binding to the alveolar epithelial cells; ❹ acute phase of ARDS, cytokine storm and likely virus entry to the circulation – systemic collapse.
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