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Review
. 2020 Oct 7:11:576745.
doi: 10.3389/fimmu.2020.576745. eCollection 2020.

ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19

Donato Zipeto  1 , Julys da Fonseca Palmeira  2 , Gustavo A Argañaraz  2 , Enrique R Argañaraz  2
Affiliations
Review

ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19

Donato Zipeto et al. Front Immunol. .

Abstract

The Coronavirus Disease 2019 (COVID-19) has already caused hundreds of thousands of deaths worldwide in a few months. Cardiovascular disease, hypertension, diabetes and chronic lung disease have been identified as the main COVID-19 comorbidities. Moreover, despite similar infection rates between men and women, the most severe course of the disease is higher in elderly and co-morbid male patients. Therefore, the occurrence of specific comorbidities associated with renin-angiotensin system (RAS) imbalance mediated by the interaction between angiotensin-converting enzyme 2 (ACE2) and desintegrin and metalloproteinase domain 17 (ADAM17), along with specific genetic factors mainly associated with type II transmembrane serine protease (TMPRSS2) expression, could be decisive for the clinical outcome of COVID-19. Indeed, the exacerbated ADAM17-mediated ACE2, TNF-α, and IL-6R secretion emerges as a possible underlying mechanism for the acute inflammatory immune response and the activation of the coagulation cascade. Therefore, in this review, we focus on the main pathophysiological aspects of ACE2, ADAM17, and TMPRSS2 host proteins in COVID-19. Additionally, we discuss a possible mechanism to explain the deleterious effect of ADAM17 and TMPRSS2 over-activation in the COVID-19 outcome.

Keywords: ACE2; ADAM17; COVID-19 pathophysiology; SARS-CoV-2; TMPRSS2.

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Figures

Figure 1
Figure 1
Pathophysiological consequences of ADAM17 over-activation in SARS-CoV-2 infection. After the binding of SARS-S to ACE2, the S-protein undergoes a proteolytic cleavage by TMPRSS2, and the virus enters the host cell. The attachment of the S protein to ACE2 triggers ADAM17 activation, increasing mACE2 downmodulation, reducing surface ACE2 expression. The increased ADAM17-mediated ACE2 shedding exacerbates the imbalance of RAS, in a looping feedback manner and increases inflammation by TNF-α the IL6 cytokine receptor (IL6R) and growth factor amphiregulin (AREG) cleavage. Finally, the sACE2 release by ADAM17 cleavage might block the viral particles entry.
Figure 2
Figure 2
Pathophysiological consequences of TMPRSS2—mediated ACE2 cleavage in SARS-CoV-2 infection. The TMPRSS2-mediated ACE2 cleavage promotes viral uptake through the cathepsin L-dependent pathway, inactivates the ACE2 membrane-bound form leaving the tissue unprotected against detrimental effect of RAS activation and does not release the soluble blocking form of ACE2.
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