Is Covid-19 severity associated with ACE2 degradation?

Bastolla, Ugo; Chambers, Patrick; Abia, David; Garc'ia-Bermejo, Maria-Laura; Fresno, Manuel

Covid-19 is particularly mild with children, and its severity escalates with age. Several theories have been proposed to explain these facts. In particular, it was proposed that the lower expression of the viral receptor ACE2 in children protects them from severe Covid. However, other works suggested an inverse relationship between ACE2 expression and disease severity. Here we try to reconcile seemingly contradicting observations noting that ACE2 is not monotonically related with age but it reaches a maximum at a young age that depends on the cell type and then decreases. This pattern is consistent with most existing data from humans and rodents and it is expected to be more marked for ACE2 cell protein than for mRNA because of the increase with age of the protease TACE/ADAM17 that sheds ACE2 from the cell membrane to the serum. The negative relation between ACE2 level and Covid-19 severity at old age is not paradoxical but it is consistent with a mathematical model of virus propagation that predicts that higher viral receptor does not necessarily favour virus propagation and it can even slow it down. More importantly, ACE2 is known to protect organs from chronic and acute inflammation, which are worsened by low ACE2 levels. Here we propose that ACE2 contributes essentially to reverse the inflammatory process by downregulating the pro-inflammatory peptides of the angiotensin and bradykinin system, and that failure to revert the inflammation triggered by SARS-COV-2 may underlie both severe CoViD-19 infection and its many post-infection manifestations, including the multi-inflammatory syndrome of children (MIS-C). Within this view, lower severity in children despite lower ACE2 expression may be consistent with their higher expression of the alternative angiotensin II receptor ATR2 and in general of the anti-inflammatory arm of the Renin-Angiotensin System (RAS) at young age.