A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury

Abstract

During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world. A new coronavirus (SARS-CoV) was identified as the SARS pathogen, which triggered severe pneumonia and acute, often lethal, lung failure. Moreover, among infected individuals influenza such as the Spanish flu and the emergence of new respiratory disease viruses have caused high lethality resulting from acute lung failure. In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor. The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses.

Collectrin and ACE2 in renal and intestinal amino acid transport

“…59 Expression at the membrane is downregulated after extracellular shedding by the ADAMs family of zinc metalloproteinases, 60 and by binding of the SARS coronavirus. 61,62 The crucial role of ACE2 in the RAS relies on its ability to cleave Ang I and Ang II to Ang (1-9) and Ang (1-7), respectively ( Fig. 2A).…”

Identification of pulmonary Oct-4 + stem/progenitor cells and demonstration of their susceptibility to SARS coronavirus (SARS-CoV) infection in vitro

“…A number of animal models have been used to study the pathogenesis of SARS-CoV infection. Although the monkey model mimics to certain degree the clinical course of SARS (16), the mouse model provides the first genetic evidence for angiotensinconverting enzyme 2 (ACE-2) as a crucial SARS-CoV receptor in vivo (17). Although type-1 pneumocytes, and to a lesser extent type-2 pneumocytes, have been shown to be the target cells of SARS-CoV infection in monkey studies (16,18), the identity of mouse bronchiolar epithelial cells infected by SARS-CoV remains unclear (19,20).…”

A Place in Our Hearts for the Lowly Angiotensin 1-7 Peptide?

“…Importantly, the increase in lung injury mediated by the Spike protein could be prevented by treating the mice with the ARB losartan. 27 Imai et al 28 extended these studies to investigate other forms of acute respiratory distress syndrome triggered by sepsis and found very similar results: lung injury (as measured by pulmonary edema, leukocyte infiltration, and increased lung elastance) was worsened in ACE2 knockout mice, whereas combined ACE and ACE2 knockout reduced the degree of lung injury to that seen in control animals. In addition, they showed that the severity of lung injury was decreased in Ang II AT 1 knockout mice and increased in AT 2 knockout mice as compared with control animals.…”

“…27 Infection with the SARS virus leads to severe pneumonia and frequently to respiratory failure. Kuba et al 27 showed that SARS surface Spike protein binds to ACE2 and causes its downregulation.…”

“…27 Infection with the SARS virus leads to severe pneumonia and frequently to respiratory failure. Kuba et al 27 showed that SARS surface Spike protein binds to ACE2 and causes its downregulation. Lavaging the lungs of mice with an acid solution resulted in lung injury that is worsened in mice pretreated with an intraperitoneal injection of SARS Spike protein.…”