SARS-CoV-2 Infection Modulates ACE2 Function and Subsequent Inflammatory Responses in Swabs and Plasma of COVID-19 Patients

Abstract

Angiotensin converting enzyme 2 (ACE2) is a host ectopeptidase and the receptor for the SARS-CoV-2 virus, albeit virus-ACE2 interaction goes far beyond viral entry into target cells. Controversial data exists linking viral infection to changes in ACE2 expression and function, which might influence the subsequent induction of an inflammatory response. Here, we tested the significance of soluble ACE2 enzymatic activity longitudinally in nasopharyngeal swabs and plasma samples of SARS-COV-2 infected patients, along with the induction of inflammatory cytokines. Release of soluble functional ACE2 increases upon SARS-CoV-2 infection in swabs and plasma of infected patients, albeit rapidly decreasing during infection course in parallel with ACE2 gene expression. Similarly, SARS-CoV-2 infection also induced the expression of inflammatory cytokines. These changes positively correlated with the viral load. Overall, our results demonstrate the existence of mechanisms by which SARS-CoV-2 modulates ACE2 expression and function, intracellular viral sensing and subsequent inflammatory response, offering new insights into ACE2 dynamics in the human upper respiratory tract and pointing towards soluble ACE2 levels as a putative early biomarker of infection severity.

Plasmatic renin-angiotensin system in normotensive and hypertensive patients hospitalized with COVID-19

“…In agreement with previous studies [6] , [7] , [8] , [9] , [16] , [27] we observed that COVID-19 patients exhibited greater sACE2 protein levels and enzymatic activity compared to healthy subjects. The increased sACE2 may reflect higher ACE2 shedding.…”

“…Regarding Ang-(1−7) levels in COVID-19 patients, some reports have shown an increase [6] , [10] , [27] while others a decrease or no change [11] , [19] , [28] . Thus, despite the fact that COVID-19 is associated with an increased ACE2 [6] , [7] , [8] , [9] , [16] , [29] , conflicting results were reported regarding Ang II and Ang-(1−7) levels [30] . Our work showed that even sACE2 activity was increased, the ratio Ang-(1−7)/Ang II was not changed in the plasma of COVID-19 patients, reflecting that the rate of conversion of Ang II into Ang-(1−7) was not modified.…”

“…ACE2 activity was measured using an ACE2-quenched fluorescent substrate (Mca-Ala-Pro-Lys(Dnp)-OH; Enzo Life Sciences) as previously described [16] . Specific activity of ACE2 was determined by addition of the ACE2 inhibitor MLN4760 (10 μmol/L).…”

Development and Validation of a Predictive Nomogram with Age and Laboratory Findings for Severe COVID-19 in Hunan Province, China

“… 7 The viral particle penetrates human cells with the help of host cell receptors and endosomes, and TMPRSS2, a serine protease, facilitates the entry, 8 resulting in various immune or inflammatory responses. 9 , 10 It has been reported that SARS-CoV-2 infection increases the expression of inflammatory cytokines, and the levels positively correlate with the viral load. 10 Patients with COVID-19 usually have symptoms of fever, shortness of breath, fatigue, and a cough; 11 , 12 nausea and vomiting are rare.…”

“… 9 , 10 It has been reported that SARS-CoV-2 infection increases the expression of inflammatory cytokines, and the levels positively correlate with the viral load. 10 Patients with COVID-19 usually have symptoms of fever, shortness of breath, fatigue, and a cough; 11 , 12 nausea and vomiting are rare. 12 About three quarters show pneumonia, some patients will go on to develop acute respiratory distress syndrome, and a few of them will show rapid worsening of symptoms and die of organ failure.…”