With New Clue to How SARS Kills, Scientists Work on Treatment

ROME, July 13 - Scientists may have solved the chemical riddle of why the SARS virus causes such a deadly pneumonia and have developed a simple therapy that promises to decrease the extraordinarily high death rate from the disease, according to a report in the issue of the journal Nature-Medicine that came out this week.

SARS, or sudden acute respiratory syndrome, spawned an epidemic of illness and fear in 2003, killing nearly 800 people worldwide and shutting down stores, airports, schools, factories and hotels across Asia, the epicenter of the outbreak, for fear that the disease would spread in crowds.

Now researchers working with mice have discovered that SARS, caused by a previously unknown member of the coronavirus family, interferes with a crucial enzyme pathway that regulates body fluid balance. By blocking that enzyme system in the lungs, the virus allows liquid to leak into the air sacs, making them boggy and inefficient.

"Now we can really understand why SARS was such a killer, compared to other viruses that are relatively harmless," said Josef Penninger, a professor at the Institute of Molecular Biotechnology of the Austrian Academy of Science, the lead author of the new paper.

The research team included scientists from Europe and Asia, who were working with mice.

But humans have the same enzyme system, called the renin-angiotensin pathway, which is crucial in both species for blood pressure and fluid regulation. If the findings can be matched in humans, the research may well lead to a new treatment for SARS - as well as for many other diseases that cause death by allowing fluid into the lungs.

In the lab, the researchers found that they could protect their SARS-infected mice from lung failure and subsequent death by giving them large amounts of angiotensin converting enzyme-2, the molecule whose function was blocked by the virus. By flooding the system with intravenous infusions of the enzyme, they could essentially overwhelm the block and its deadly effects.

Scientists already know how to manufacture a synthetic version, making the move from lab animals to human therapy relatively straightforward. "We are pretty confident that this is relevant to humans and a treatment could be available in another two to three years," Dr. Penninger said.

The discovery could have broader implications, since the type of lung damage caused by SARS is found in other deadly diseases. SARS victims die because their lungs fill with fluid, a condition known as acute respiratory distress syndrome.

The SARS virus is just one cause of the syndrome, a currently untreatable condition that causes up to a million deaths worldwide each year. It can also result from cancers, burns and infections including bird flu, which many epidemiologists believe will be the next big disease outbreak in Asia.

"SARS may have put us on the trail of a new therapy that could be used for many diseases," Dr. Penninger said.

Last year, doctors studying the newly identified SARS virus were at first surprised and confused to find that the virus bound to a receptor in the renin-angiotensin system, a pathway not previously associated with the lungs. Subsequent research found that receptors for the system exist in the lungs and the intestines.

But some scientists cautioned that it remained to be determined if all cases of respiratory distress syndrome were caused by disturbances in the same enzyme pathway and whether the mouse model was relevant to humans.

"Infection in mice does not produce the typical picture seen in human disease," cautioned John Nicholls, a researcher at the University of Hong Kong, in a commentary accompanying the report.

Still, he acknowledged that the research might be "particularly relevant as we prepare to confront a potential avian flu epidemic, armed with only a limited number of therapeutic options."