An international research group lead by IMBA’s Josef Penninger found out which molecular mechanisms make SARS – the virus that triggered a worldwide health crisis in 2003 – such a deadly threat. The groundbreaking research results point at ways to treat SARS and other dreaded diseases such as avian flu or Anthrax.

During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly from China throughout Asia to Canada and beyond, causing almost 800 deaths and disrupting travel, economics, and even scientific conventions. A novel coronavirus was identified as the SARS pathogen which triggered atypical pneumonia characterized by high fever and severe dyspnea.

In two papers that were published in subsequent issues of Nature and Nature Medicine, the research group lead by Dr. Penninger - including postdoctoral fellows Yumiko Imai and Keiji Kuba in collaboration with researchers in Beijing, Toronto, and Vienna – has now found out that a key role in the infection – and in triggering the lung failure - is played by ACE2 (angiotensin converting enzyme 2), a protein well known for its role in regulating blood pressure.

Dr. Penninger and his team for the first time succeeded to genetically prove in vivo that ACE2 is a crucial SARS receptor. Their work provides a molecular explanation why and how SARS infections cause severe and often lethal lung failure.

But the significance of the findings extends far beyond SARS infections. SARS as well as a number of other killers have in common that they usually trigger pneumonia and acute, often lethal, lung failure. The lung gets flooded as its blood vessels leak, and it fills with body secretions. As a consequence, acute lung failure is a cause of death not only in SARS but in many other diseases such as sepsis, aspiration of gastric contents in newborns or patients in intensive care units, or patients with pancreatitis. Importantly, acute lung failure is also the principle that kills in avian flu, the famous Spanish flu of the early 20th century, and lung infections caused by the potential bioterrorism agent anthrax.

The current studies show that ACE2 not only plays a role in SARS mediated lung failure. It protects mice just as well against severe acute lung failure induced by acid aspiration or sepsis.

Based on their new understanding of SARS infections and SARS triggered lung failure, the researchers succeeded in designing a novel rational therapy approach (that is, a cure aiming at the cause of diseases). They managed to effectively treat acute lung failure in mice with recombinant ACE2 and abolished the lung failure effects of SARS proteins by modulating the ACE2 pathway.

These findings could provide the key for a rational therapy that may help millions of people affected with a previously untreatable disease.

SARS emerged in mid-November 2002 in Guangdong Province in Southern China. With an estimated incubation period lasting less than 14 days, the coronavirus spread with surprising speed and soon infected approximately 1290 people with 55 reported deaths in Mainland China alone. Within a short time, 27 countries on 6 continents began to report illnesses.

The death rate following infection approached almost 10 percent due to the development of acute respiratory distress syndrome (ARDS). Moreover, influenza such as the Spanish flu and the emergence of new respiratory disease viruses have caused high lethality among infected individuals due to ARDS. The high lethality of SARS infections, its enormous economic and social impact, fears of renewed outbreaks of SARS as well as the dreaded misuse of such viruses as biologic weapons make it paramount to understand the disease pathogenesis of SARS and ARDS.

Based on the fact that ACE2 as a receptor is present in the lungs, the team around Dr. Penninger wondered whether ACE2 played a role in SARS pathogenesis – that is, acute lung failure. Subsequently, it could be shown that ACE2 protects against acute lung failure and lung oedema in models of sepsis, aspiration of acid contents and in a model of SARS-induced acute lung failure. ACE2 appears as a common injury pathway in multiple diseases that result in acute lung oedema.

ACE2, an enzyme known for its role in controlling blood pressure and even in heart failure, in this context appears in a completely new function within the renin-angiotensins system, with a novel and essential function in the lungs to control oedema and acute lung failure.