ACE2 and COVID-19: It is therefore hypothesized that two hits contribute to the hyper-inflammatory response that is observed in COVID-19 patients with comorbidities; the first hit was resulting from the chronic state of inflammation, which increases the activity of the ATII proinflammatory axis, and the second hit resulting from SARS-CoV-2 itself, via the internalization of ACE2 receptors, and the decrease in the activity of the anti-inflammatory ACE2 axis [253].