The differential expression of the ACE2 receptor across ages and gender explains the differential lethality of SARS-Cov-2 and suggests possible therapy

Bastolla, Ugo

The fatality rate of SARS-Cov-2 escalates with age and is larger in men than women. I show that these variations are strongly correlated with the levels of the ACE2 protein in the lungs but surprisingly, despite ACE2 is the viral receptor, higher levels lead to lower fatality. This behaviour is consistent with a previous mathematical model that predicts that the speed of viral progression in the organism has a maximum and then declines with the receptor level. SARS-Cov-2 degrades ACE2 and thus worsens lung injury, causes vasoconstriction, thrombotic problems, and exacerbated inflammatory response. I developed a mathematical model based on the influence of ACE2 on viral propagation and on the negative effects of its degradation. The model fits SARS-CoV-2 fatality rate across age and gender with high accuracy ($r^2>0.9$). Rescaling the model parameters with the binding rates of the spike proteins of SARS-CoV and SARS-CoV-2 allows predicting the fatality rate of SARS-CoV across age and gender, in particular its higher severity for young patients, thus linking the molecular and epidemiological levels. These results support the suggestion that drugs that enhance the expression of ACE2, such as ACE inhibitors and angiotensin receptor blockers, constitute a promising therapy against the most adverse effects of CoViD-19. Furthermore, ACE2 is a candidate prognostic factor for detecting population that needs stronger protection.