Severe acute respiratory syndrome (SARS), an illness identified in 2003 that spread throughout the world for several months, re-awakened nightmares of a lethal global pandemic. Caused by the SARS coronavirus (SARS-CoV), therapeutic options are limited, and fears of renewed outbreaks highlight the paramount importance of understanding its pathogenicity. Reporting in Nature Medicine, a multinational research team now provides a molecular explanation for the high lethality associated with SARS, and highlight a potential therapeutic strategy for tackling SARS and possibly other respiratory disease viruses.

Recently, the renin–angiotensin system, an endocrine cascade best known for regulating blood pressure, has been implicated in the respiratory damage responsible for SARS lethality. Angiotensin II, which is produced through the action of angiotensin-converting enzyme (ACE), has been identified as a potent vasoconstrictor that can aggravate lung injury and produce lung oedema.

Intriguingly, in vitro experiments have indicated that ACE2 — a homologue of ACE that negatively regulates angiotensin II — is a cellular receptor for SARS-CoV. Now, by using mice deficient for ACE2, Kuba et al. provide the first in vivo evidence for the importance of this enzyme in SARS-CoV replication, and show that infection with SARS leads to downregulation of ACE2. The authors identified the SARS-CoV Spike protein as an interaction partner for ACE2, and demonstrated that recombinant Spike exacerbates acute lung injury through down-modulation of ACE2 and subsequent accumulation of angiotensin II. Recombinant ACE2, as well as angiotensin II receptor type 1 (AT1R) inhibitors, which are already in clinical use for the control of blood pressure, were shown to protect against Spike-mediated lung injury in mice.

Underscoring the relevance of these findings in humans, recent data in a small cohort of individuals with SARS suggested that an insertion deletion ACE polymorphism that affects ACE function correlates with disease severity. Furthermore, the SARS-CoV–ACE2 interaction might also provide a molecular explanation for the long-standing puzzle as to why SARS-CoV is so much more lethal than other coronavirus infections, which are responsible for 30% of common colds.

These findings are a crucial step towards the development of treatments for individuals infected with SARS-CoV. Furthermore, evidence of the link between the renin–angiotensin system and acute lung failure could also provide an opportunity to treat other viral infections that owe their lethality to a respiratory syndrome — for example the avian influenza A H5N1 strain, whose recent outbreak in South East Asia resulted in 70% lethality due to acute respiratory failure.