ACE2 in SARS-CoV infections of the lung
In a landmark study, using mouse models of acid-respiration or LPS, the Penninger group initially showed a protective role of ACE2 in ARDS (Imai et al., 2005) and demonstrated that ACE1-mediated signaling promotes ARDS but ACE2 exerts strong protective effects. ACE2 knockout (KO) mice had dramatically increased lung injury, effects that were reduced by treating with recombinant human ACE2. Conversely, ACE-deficient mice had reduced severity of injury, supporting the concept that ACE1/ACE2 balance is a central mediator of lung injury.
The Penninger group subsequently used ACE2 KO mice and found that ACE2 expression is necessary for SARS infection (Kuba et al., 2005). The authors hypothesized that RAS signaling blockade or treatment with recombinant ACE2 would protect from SARS-induced injury. A crucial observation was that SARS-CoV-infected mice resembled ACE2 KO mice in their susceptibility to lung injury (Kuba et al., 2006). Penninger and coworkers have extended these ideas to COVID-19, advocating for the use of ACE2 as a target in SARS-CoV-2, including by providing soluble ACE2 (Zhang et al., 2020). The Penninger group recently showed the efficacy of recombinant human ACE2 in drastically reducing the infectivity of SARS-CoV-2 in ex-vivo models, including with organoids (Monteil et al., 2020).