Figure 8

A theoretical model for Sars-Cov-2 pathogenesis. (a) Schematic representation of the identified alveolar epithelium progeny, with AT2 precursors giving rise to club and AT2-signaling cells. The latter then gives rise to pro-ciliated and ciliated cells, whereas the latter give rise to basal, mucous and AT1 precursor cells. AT1 precursors which are ACE2-/KNG1+ /KLKB1+ give rise to mature AT1 cells, which highly express ACE2 during their differentiation process. Selective disruption of the alveolar niche turnover dynamics could thus be implicated in Sars-Cov-2 pathogenesis, and we encourage further studies investigating these associations. (b) Schematic representation of the healthy alveolus prior to Sars-Cov-2 binding to ACE2 (1). Either by structural ACE2 changes or by disruption of the ACE2+ population, Sars-Cov-2 infection potentially interferes with two key ACE2 roles: (2a) converting Ang II to Ang 1–7, thus compromising alveolar cell survival signaling; and (2b) degradation of bradykinin into inactive products. Pro-AT1 (club) cells highly and selectively express kininogen and kallikrein (3), which jointly leads to the production of bradykinin. Kallikrein is also involved in converting plasminogen into plasmin (not shown). Infection derived disruption of the alveolar niche with selective preservation of ACE2-/KNG1+ /KLKB1+ pro-AT1 club cells could be associated with disturbance of the KKS, leading to severe inflammation and altered coagulation.