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).