  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.
