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

By K. Kuba, Y. Imai, Shuan Rao, Hong Gao, F. Guo, Bin Guan, Yi Huan, Peng‐fei Yang, Yanli Zhang, Wei Deng and 14 more. Nature Medicine, 2005

3,326 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/d99cfca5014e00d83bfe76ea156cc7af18d9da95

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In Epidemiology

1. T. Hirano
2. S. Perlman
3. Andreas Nitsche
4. Ramnik J. Xavier
5. Yibin Wang
6. T. Guzik
7. Rhian M. Touyz
8. S. Ghasemi

In Infectious Diseases

1. Kwok-Yung Yuen
2. S. Weiss
3. S. Perlman
4. T. Hirano
5. V. Munster
6. J. Leibowitz
7. Susanna K. P. Lau
8. V. Cheng

Citations in the corpus

• SARS and MERS: recent insights into emerging coronaviruses (2016, positive): “The binding of spike protein to ACE2 and the subsequent downregulation of this receptor contribute to lung injury during SARS 45 .”
• SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor (2020, background): “Finally, it should be noted that ACE2 expression protects from lung injury and is downregulated by SARS-S (Haga et al., 2008; Imai et al., 2005; Kuba et al., 2005), which might promote SARS.”
• Coronavirus Pathogenesis (2011, background): “ACE2 has a pneumoprotective effect on acute lung injury induced by acid injury (Imai et al., 2005), and instillation of a recombinant fusion protein containing the SARS S protein RBD increased acute lung injury by acid (Kuba et al., 2005).”
• Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC (2013, positive): “Downregulation of ACE2 expression after SARS-CoV infection has been shown to contribute to the severity of disease 22 , consistent with the protective role of soluble ACE2 in lung injury 23 .”
• COVID-19 and diabetes: Knowledge in progress (2020, positive): “Mice injected with SARS-CoV Spike presented worsened acute lung failure, which could be attenuated by blocking the renin-angiotensin pathway [59].”
• Efficient Activation of the Severe Acute Respiratory Syndrome Coronavirus Spike Protein by the Transmembrane Protease TMPRSS2 (2010, background): “This inconsistency may be explained by the downregulation of ACE2 in SARS-CoV-infected cells, as previously reported (11, 17).”
• Coronavirus disease 2019 (COVID-19): current status and future perspectives (2020, background): “The causes of different infection sites are likely related to the presence of dipeptidyl peptidase 4 (DPP4) and angiotensin-converting enzyme 2 (ACE2) in the lower respiratory tract, which are the major human receptors for the surface spike (S) glycoprotein of MERS and SARS-CoV, respectively [22-24]”
• Immune Response, Inflammation, and the Clinical Spectrum of COVID-19 (2020, background): “SARS-CoV infection induces autophagy (51, 52), detachment of the basal membrane, and inhibition of ACE2 expression (20, 53), hence allowing angiotensin II to bind the AT1aR receptor, resulting in acute lung”
• A Review of SARS-CoV-2 and the Ongoing Clinical Trials (2020, background): “Once angiotensin II binds to its receptor, AGTR1A, pulmonary vascular permeability is increased [39].”