Infection by the SARS-CoV-2 virus is mediated by the binding of its spike protein to the membrane-bound angiotensin converting enzyme 2 (ACE2), which plays a pivotal role in the renin-angiotensin system (RAS). The understanding of RAS dysregulation due to this viral infection is of fundamental importance to better understand the pathogenic mechanisms and risk factors of the coronavirus diseaseCOVID-19 , and to design effective therapeutic strategies. To address this issue, we built a mathematical model of RAS based on data about protein and peptide concentrations in normotensive and hypertensive individuals. We first tested our model on clinical data on the action of antihypertensive RAS-blocking drugs in control individuals. Despite the simplicity of our model, it reproduces very well, without any fitting of additional parameters, the impact of a series of drugs, i.e. angiotensin-converting enzyme inhibitors (ACE-I), direct renin inhibitors (DRI) and angiotensin II receptor blockers (ARB). We applied our model to analyze the impact of SARS-CoV-2 infection on the RASsystem , which we modeled through a downregulation of ACE2 related to viral load. Moreover, we analyzed the effect of RAS-blockers and other RAS-targeting drugs, i.e. human recombinant ACE2 (rhACE2) and angiotensin 1-7 peptide (Ang1-7), on the RAS system of normotensive and hypertensive COVID-19 patients . We found that while ACE-I, DRI, rhACE2 and Ang1-7 tend to improve the clinical outcomes in a tension-dependent manner, the use of ARB appears to worsen it. The mathematical model that we developed offers the interesting possibility of testing in silico the RAS dysregulation upon SARS-CoV-2 infection and of predicting how risk factors as well as different drugs , alone or in combination, impact on RAS and disease severity .
 SARS-CoV-2 coronavirus infection is mediated by the binding of its spike protein to the angiotensin-converting enzyme 2 (ACE2), which plays a pivotal role in the renin-angiotensin system (RAS). The study of RAS dysregulation due to SARS-CoV-2 infection is fundamentally important for a better understanding of the pathogenic mechanisms and risk factors associated with COVID-19 coronavirus disease , and to design effective therapeutic strategies. In this context, we developed a mathematical model of RAS based on data regarding protein and peptide concentrations ; the model was tested on clinical data from healthy normotensive and hypertensive individuals. We then used our model to analyze the impact of SARS-CoV-2 infection on RAS , which we modeled through a down-regulation of ACE2 as a function of viral load. We also used it to predict the effect of RAS-targeting drugs, such as RAS-blockers, human recombinant ACE2 , and angiotensin 1-7 peptide , on COVID-19 patients ; the model predicted an improvement of the clinical outcome for some drugs and a worsening for others .
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