SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Hoffmann, Markus; Kleine-Weber, Hannah; Schroeder, Simon; Krüger, Nadine; Herrler, Tanja; Erichsen, S.; Schiergens, Tobias S.; Herrler, Georg; Wu, Nai Huei; Nitsche, Andreas; Müller, Marcel A.; Drosten, Christian; Pöhlmann, Stefan

doi:10.1016/j.cell.2020.02.052

Cited by 18,588 publications

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“…[5] ACE2 is a type 1 integral membrane glycoprotein expressed in the epithelial cells of cardiovascular, pulmonary, renal, brain and intestinal tissue, it acts by breaking down angiotensin II into angiotensin 1-7. [37,39,40] This enzyme acts by counteracting the inflammatory actions of angiotensin II, lowering the concentration of pro-inflammatory cytokine interleukin (IL)-6, increasing the anti-inflammatory, and increasing the antioxidant action of angiotensin 1-7, escalating the levels of surfactant protein D and promoting vasodilation. [41] The novel coronavirus responsible for COVID-19 is expected to act similary to Severe Acute Respiratory Syndrome (SARS-CoV).…”

Section: Discussionmentioning

confidence: 99%

“…[39] Viral surface spike (S) protein of COVID-19 binds to ACE2 after spike protein activation by transmembrane protease serine 2 (TMPRSS2). [40] Routine use of ACEI and ARB as a medication for chronic conditions upregulates ACE2 expression, [5,37] thereby facilitating entry of SARS-CoV-2 into the pneumocytes and consequently cause severe and fatal infection. [42] Among other diabetic medications, the use of liraglutide and pioglitazone have also been found to be related with increased ACE2 regulation in animal studies.…”

Section: Discussionmentioning

confidence: 99%

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Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia – A systematic review, meta-analysis, and meta-regression

Huang

Lim

Pranata

2020

Diabetes & Metabolic Syndrome: Clinical Research & Revi

818

747

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Background and AimsDiabetes Mellitus (DM) is chronic conditions with devastating multi-systemic complication and may be associated with severe form of Coronavirus Disease 2019 . We conducted a systematic review and meta-analysis in order to investigate the association between DM and poor outcome in patients with COVID-19 pneumonia. MethodsSystematic literature search was performed from several electronic databases on subjects that assess DM and outcome in COVID-19 pneumonia. The outcome of interest was composite poor outcome, including mortality, severe COVID-19, acute respiratory distress syndrome (ARDS), need for intensive care unit (ICU) care, and disease progression. ResultsThere were a total of 6452 patients from 30 studies. Meta-analysis showed that DM was associated with composite poor outcome (RR 2.38 [1.88,3.03], p<0.001; I 2 : 62%) and its subgroup which comprised of mortality (RR 2.12 [1.44, 3.11], p<0.001; I 2 : 72%), severe COVID-19 (RR 2.45 [1.79, 3.35], p<0.001; I 2 : 45%), ARDS (RR 4.64 [1.86,11.58], p=0.001; I 2 : 9%), and disease progression (RR 3.31 [1.08, 10.14], p=0.04; I 2 : 0%). Meta-regression showed that the association with composite poor outcome was influenced by age (p=0.003) and hypertension (p<0.001). Subgroup analysis showed that the association was weaker in studies with median age ≥55 years-old (RR 1.92) compared to <55 years-old (RR 3.48), and in prevalence of hypertension ≥25% (RR 1.93) compared to <25% (RR 3.06). Subgroup analysis on median age <55 years-old and prevalence of hypertension <25% showed strong association (RR 3.33) ConclusionDM was associated with mortality, severe COVID-19, ARDS, and disease progression in patients with COVID-19.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia – A systematic review, meta-analysis, and meta-regression

Huang

Lim

Pranata

2020

Diabetes & Metabolic Syndrome: Clinical Research & Revi

818

747

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“…Increased ACE-2 expression may not result in more viral entry into the cell because of the limited availability of the serine protease TMPRSS2. Camostat mesylate, which is a TMPRSS2 inhibitor, has been shown to inhibit cellular entry of SARS CoV2 and could be a potential therapeutic option [43]. ii.…”

Section: Effects Of Ace Inhibitors and Angiotensin Receptor Blockersmentioning

confidence: 99%

Comorbidities in COVID-19: Outcomes in hypertensive cohort and controversies with renin angiotensin system blockers

Singh

Gupta

Misra

2020

Diabetes & Metabolic Syndrome: Clinical Research & Revi

222

156

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a b s t r a c tBackground and aims: COVID-19 is already a pandemic. Emerging data suggest an increased association and a heightened mortality in patients of COVID-19 with comorbidities. We aimed to evaluate the outcome in hypertensive patients with COVID-19 and its relation to the use of renin-angiotensin system blockers (RASB). Methods: We have systematically searched the medical database up to March 27, 2020 and retrieved all the published articles in English language related to our topic using MeSH key words. Results: From the pooled data of all ten available Chinese studies (n ¼ 2209) that have reported the characteristics of comorbidities in patients with COVID-19, hypertension was present in nearly 21%, followed by diabetes in nearly 11%, and established cardiovascular disease (CVD) in approximately 7% of patients. Although the emerging data hints to an increase in mortality in COVID-19 patients with known hypertension, diabetes and CVD, it should be noted that it was not adjusted for multiple confounding factors. Harm or benefit in COVID-19 patients receiving RASB has not been typically assessed in these studies yet, although mechanistically and plausibly both, benefit and harm is possible with these agents, given that COVID-19 expresses to tissues through the receptor of angiotensin converting enzyme-2. Conclusion: Special attention is definitely required in patients with COVID-19 with associated comorbidities including hypertension, diabetes and established CVD. Although the role of RASB has a mechanistic equipoise, patients with COVID-19 should not stop these drugs at this point of time, as recommended by various world organizations and without the advice of health care provider.

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“…A recent study used some serine protease TMPRSS2 inhibitors to prevent the virus from entry to the cell. These compounds are clinically approved and potentially will reduce the virus replication [8]. Some FDA approved anthelminthic compounds such as niclosamide have potent antiviral effects not only for SARS-CoV-2 but also for other viruses, including SARS-CoV, MERS-CoV, Zika virus, and HCV [63].…”

Section: Strategies Based On the Development Of Novel Vaccines And Anmentioning

confidence: 99%

“…In recent studies, it is apparent that SARS-CoV-2 uses the mechanism that SARS-CoV used for cell entry. The mechanism of the virus entry to the cell resulting from the interaction between the virus receptors and the spike glycoprotein, after priming of that viral protein by the Serine protease TMPRSS2 [8]. Further, inhibition of TMPRSS2, blocked cell entry by SARS-CoV-2, indicating similar or identical pathways for cell invasion and possible strategies for therapeutics [8].…”

mentioning

confidence: 99%

The SARS-CoV-2 outbreak from a one health perspective

Hemida

Abduallah

2020

One Health

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The SARS-CoV-2 is a new human coronavirus candidate recently detected in China that is now reported in people on inhabited continents. The virus shares a high level of identity with some bat coronaviruses and is recognised as a potentially zoonotic virus. We are utilizing the One Health concept to understand the emergence of the virus, as well as to point to some possible control strategies that might reduce the spread of the virus across the globe; thus, containment of such virus would be possible. J o u r n a l P r e -p r o o f Journal Pre-proof J o u r n a l P r e -p r o o f Journal Pre-proof J o u r n a l P r e -p r o o f Journal Pre-proof J o u r n a l P r e -p r o o f Journal Pre-proof J o u r n a l P r e -p r o o f Journal Pre-proof

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SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Abstract: Graphical AbstractHighlights d SARS-CoV-2 uses the SARS-CoV receptor ACE2 for host cell entry d The spike protein of SARS-CoV-2 is primed by TMPRSS2 d Antibodies against SARS-CoV spike may offer some protection against SARS-CoV-2

Cited by 18,588 publications

References 60 publications

Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia – A systematic review, meta-analysis, and meta-regression

Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia – A systematic review, meta-analysis, and meta-regression

Comorbidities in COVID-19: Outcomes in hypertensive cohort and controversies with renin angiotensin system blockers

The SARS-CoV-2 outbreak from a one health perspective

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