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November 26, 2003
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Reserchers Find Way To Block The SARS Virus From Entering Cells
Discovery of SARS receptor may lead to a vaccine and treatment
Researchers at Children's Hospital Boston, Brigham and Women's Hospital (BWH), Harvard Medical School, and the University of Massachusetts Medical School have, for the first time, discovered a specific receptor on cells that opens the door to the SARS virus, allowing the virus to bind, enter, and then replicate. Finding this receptor, known as ACE2, is a first step in what is hoped will be a major advance in the diagnosis and treatment of SARS. The findings appear in the November 27th issue of Nature.
SARS - severe acute respiratory syndrome - is a viral respiratory illness caused by a distinct form of coronavirus, a family of viruses also implicated in the common cold. SARS was first identified in Asia in February 2003 and eventually caused a worldwide outbreak over a span of a few months. In all, 8,098 people contracted SARS, of whom 774 died, according to the World Health Organization. Although the outbreak is now under control, there are fears that the SARS virus may return this winter.
''Identification of the receptor ACE2 (angiotensin-converting enzyme 2) is like discovering the lock that is a perfect fit for the SARS virus key,'' said Michael Farzan, PhD, a BWH microbiologist and assistant professor at Harvard Medical School. ''Pinpointing exactly where the virus attaches itself to the cell and understanding how this happens makes it much easier to find ways we can block the virus before it infects.''
The institutions collaborated closely as the research unfolded. To understand how the SARS virus enters the cell, Farzan, Wenhui Li from BWH, and Hyeryun Choe, PhD, an assistant professor in the Children's Hospital Boston pulmonary department, needed to identify two parts to the binding process ? first, the protein on the virus that acted as the key and second, the receptor on the cell that acted as the lock. With access to the SARS genome, successfully mapped in April 2003 only months after the virus was first identified, one of the pieces to the puzzles was instantly solved -- the spike (S1) protein served as the virus' key. BWH researchers developed a technique for generating the spike protein in the laboratory without having to actually use the virus (which makes spike protein only in miniscule amounts). ''If we were dependent on the SARS virus' natural design, we wouldn't have had enough spike protein to work with,'' says Choe.
The research then moved to the University of Massachusetts Medical School, where cells were exposed to live SARS virus. The virus thrived in cells that carried the ACE2 receptor, but was unable to replicate in cells without ACE2. In a second set of experiments, Farzan and his colleagues looked at ways to block the receptor, or fill the lock so that the key could not be inserted. They discovered that by introducing antibodies against ACE2, the virus? spike protein could be prevented from binding to the surface of the cell. This finding provides important clues for possible treatments to act as a barrier to infection, stopping the virus from taking hold in the body.
The lungs, kidneys, and gastrointestinal tract have all been shown to be sites of SARS virus replication, and all carry the ACE2 receptor. ''The expression of ACE2 in human tissues matches very closely to what one expects of a receptor for the SARS virus,'' said Choe.
With anxiety that SARS may reemerge in the coming months, these findings have potential to play a major role in controlling the disease. Choe predicts a rush to screen inhibitory drugs that might block the ACE2 receptor. ''Immediately, we can begin testing soluble forms of the receptor and ACE2 antibodies as possible treatments and identify which animals act as carriers of the virus,'' adds Farzan, noting that rodents are an unlikely source of the virus because their ACE2 does not support replication. ''Our longer term goal will be to apply this information to make a vaccine.''
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults for more than 130 years. More than 500 scientists, including seven members of the National Academy of Sciences, nine members of the Institute of Medicine and nine members of the Howard Hughes Medical Institute comprise Children's research community. Founded in 1869 as a 20-bed hospital for children, Children's Hospital Boston today is a 300-bed comprehensive center for pediatric and adolescent health care grou'ded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. It is also the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital visit: www.childrenshospital.org.
BWH is a 725-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare System, an integrated health care delivery network. Internationally recognized as a leading academic health care institution, BWH is a leading recipient of research grants from the National Institutes of Health, BWH conducts internationally acclaimed clinical, basic and epidemiological studies.