Abstract
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-19. However, other works suggested an inverse relationship between ACE2 expression and disease severity. Here we review the seemingly contradicting observations on ACE2 expression at the levels of mRNA, membrane protein and serum protein in humans and rodents and try to reconcile them at the light of the Renin-Angiotensin system (RAS) and bradykinin system, which constitute an integrated inflammatory system connected by common peptidases and interacting receptors. We find that ACE2 level is not monotonically related with age but it reaches a maximum at a young age that depends on the cell type and then decreases, consistently with almost all existing data. The increase with age of the protease Tumor necrosis factor alpha (TNF-α) converting enzyme (TACE), also known as ADAM17 (a disintegrin and metalloproteinase 17) that sheds ACE2 from the cell membrane to the serum predicts that the decrease occurs before and is steeper for ACE2 cell protein than for its mRNA. This negative relation between ACE2 level and Covid-19 severity at old age is not paradoxical but it is consistent with a mathematical model that predicts that higher viral receptor does not necessarily favour virus propagation and it can even slow it down. More importantly, the angiotensin-bradykinin system is characterized by a powerful positive feedback loop that enhances inflammation through the Angiotensin and Bradykinin receptors that upregulate ADAM17, which in turn downregulates ACE2 and upregulates TNF-α and the pro-inflammatory receptor of the cytokine interleukin 6 (IL6). Here we propose that ACE2 contributes essentially to reverse this inflammatory state by downregulating the pro-inflammatory peptides of the angiotensin-bradykinin system, and that failure to do this, possibly induced by the degradation of ACE2 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 RAS at young age.
Highlights
The Covid-19 pandemics (Zhou et al, 2020) has overcome four million confirmed deaths (Dong et al, 2020), and excess death indicates that the real number may be substantially higher
We find that Angiotensin converting enzyme 2 (ACE2) level is not monotonically related with age but it reaches a maximum at a young age that depends on the cell type and decreases, consistently with almost all existing data
As reviewed above by us and elsewhere by many other authors, the peptidase ACE2, besides being the cellular receptor of SARSCOV-2 and other coronavirus, exerts a central regulatory role in inflammatory processes by downregulating the main proinflammatory peptides of the Renin-angiotensin system (RAS) and the Kinin kallikrein system (KKS) (Figure 3). These two highly integrated signalling systems, whose receptors act synergistically and strengthen each other, activate the inflammatory response, activate cytokines starting from a central controller of inflammation such as TNF-α, which is activated by the same protease TACE/ ADAM17 that degrades ACE2 and recruits macrophages and neutrophils
Summary
The Covid-19 pandemics (Zhou et al, 2020) has overcome four million confirmed deaths (Dong et al, 2020), and excess death indicates that the real number may be substantially higher. Hypotension: 66% of critical patients (Michard and VieillardBaron, 2020), and 8% of hospitalized patients compared with 39% with hypertension (Lala et al, 2020) Both bradykinin and Angiotensin II upregulate the protease ADAM17/TACE that removes ACE2 from the cell membrane, activates TNF-α and transforms the receptor of the cytokine IL6 to a soluble form that enhances inflammation (Matthews et al, 2003; Rose-John, 2012). The shape of this curve appears inversely related to the ACE2 protein level across age (Figure 4A), the position of the maximum of ACE2 depends on the cell type Another recent paper analysed similar data but proposed a direct instead of inverse relationship between Covid-19 severity and ACE2 expression (Inde et al, 2020). Experimental verifications of the above hypothesis are necessary, and clinical trials are urgently needed to test these therapeutic indications
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