BioWorld International Correspondent

LONDON - The receptor for the severe acute respiratory syndrome virus on mammalian cells is angiotensin-converting enzyme 2 (ACE2), an international team of researchers working in Austria has found.

The discovery has allowed the team to pinpoint exactly how the SARS coronavirus causes deadly acute lung failure. The outcome, they predict, will be new treatments for acute lung failure, whether caused by SARS, influenza virus, pneumonia or sepsis.

Josef Penninger, director of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences in Vienna, told BioWorld International: "As a result of SARS revealing its secrets of how it damages the lungs, it may also have shown us how to develop new medicines to treat other diseases that involve acute lung failure."

In summary, the team has shown that the SARS virus binds to ACE2, that levels of ACE2 in the lungs of mice infected with SARS virus are low, and that recombinant ACE2 can protect mice from severe acute lung injury.

Although the experiments to date have been carried out only in mice, Penninger described the development as "very promising." He has set up a company in Vienna, Apeiron Biologics, to make recombinant ACE2 protein and begin clinical trials to evaluate its use in treating acute lung failure in humans.

The work is reported in two papers. The first, in the July 7, 2005, issue of Nature, is titled "Angiotensin-converting enzyme 2 protects from severe acute lung failure." The second, in the July 10, 2005, issue of Nature Medicine, is titled "A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury."

Commenting in Nature on both papers, John Nicholls and Malik Peiris, of the department of pathology and the department of microbiology, respectively, at the University of Hong Kong, wrote: "Clearly, the potential therapeutic utility of recombinant ACE2 and angiotensin II receptor inhibitors - already in clinical use for control of blood pressure - for acute lung injury resulting from viruses and other causes will be a productive field for investigation."

In their News and Views article, titled "Good ACE, bad ACE do battle in lung injury, SARS," they conclude that the finding is "particularly relevant as we prepare to confront a potential avian flu pandemic, armed with only a limited number of therapeutic options."

ACE2 is one of the components of the renin-angiotensin system, which plays a key role in maintaining blood pressure levels, including the regulation of salt and fluid balance. ACE2 converts angiotensin II to angiotensin1-7. The latter causes blood vessels to dilate. ACE, by contrast, converts angiotensin I to angiotensin II, which makes blood vessels constrict. The effects of ACE and ACE2 on heart function counterbalance each other.

Penninger and his colleagues made the first knockout mouse lacking functional ACE2 in 2002. As they age, those mice develop progressive heart function abnormalities. When other researchers reported that ACE2 might be a receptor for the SARS virus, Penninger's group decided to examine the animals' lungs in more detail - and found that following injury they developed acute lung failure.

Penninger said: "This was completely unexpected, a really novel finding. It also fit with the observation that, in patients with acute respiratory distress syndrome, you find more ACE expression in the lungs."

In the latest study, Penninger, working with a team of scientists from China, Japan, Canada and Germany, as well as colleagues in Austria, tried to establish if ACE2 is the receptor for the SARS virus. The group infected ACE2 knockout mice and a control group of wild-type mice with the SARS coronavirus. They found that the knockout mice suffered fewer harmful effects in the lungs than the wild-type mice, and could find only very low levels of the virus in the lungs of the knockout mice. Writing in Nature Medicine, they concluded that their data provide "the first genetic proof that ACE2 is indeed a crucial in vivo SARS receptor required for effective replication" of the SARS coronavirus.

In the Nature paper, the same group described how ACE2 can protect mice from experimentally induced severe acute lung injury.

Penninger added that his team's findings also fit with a discovery by another group, who studied a small group of people with SARS, that a polymorphism in the gene encoding ACE, which affected the function of the molecule, correlated with the degree of severity of the illness.

"This suggests to us that our findings are indeed relevant for humans," he concluded.