RESEARCHERS FIND RECEPTOR THAT SARS VIRUS USES TO INFECT CELLS

Discovery of ACE2 as receptor for SARS may lead to a vaccine and treatment for the deadly respiratory disease

November 26, 2003

WORCESTER, Mass.— A team of researchers at the University of Massachusetts Medical School, Harvard University and several Boston teaching hospitals, has found that angiotensin-converting enzyme 2 (ACE2) is a functional receptor that allows the SARS virus to infect human cells.

The discovery identifies a likely target for developing therapeutics and designing vaccines effective against the virus that causes severe acute respiratory syndrome (SARS).  Details of the finding were published November 27 in the journal Nature.  

“We think this is a critical step forward in the research into SARS,” said Thomas C. Greenough, MD, assistant professor of pediatrics and medicine at UMMS, a co-author of the paper. “Once you understand how SARS gets into the cell, you open up avenues for developing treatment strategies and vaccines.”

The UMMS team worked with researchers at Harvard University, Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Children’s Hospital of Boston on the SARS ACE2 study.  Led by Harvard’s Michael Farzan, PhD, the Boston-based team began searching for possible SARS receptors earlier this year by using elements of the “Spike” or S protein, which the virus uses like a hook to grab onto cells.  Dr. Farzan’s team synthesized the S protein and attached a molecular handle to it. They then exposed cells that the virus is known to infect to this synthetic S protein and used the molecular handle to isolate and identify cellular proteins that bound to it tightly.  One of the proteins that bound was ACE2.  Dr. Farzan’s team went on to show that the interaction between s protein and ACE2 enables cell membranes to fuse together, a process that is critical for a virus to enter a cell.

The work then moved to labs at UMMS where Dr. Greenough and others tested ACE2 with the live SARS virus. Using two separate approaches, the UMMS team confirmed that indeed the ACE2 receptor was key for the SARS virus to infect cells and replicate itself.  “Using tissue culture, we were able to show that the virus replicated to levels 100,000 times more in the presence of cells expressing ACE2, than in the presence of those that did not express ACE2,” Dr. Greenough said.  The UMMS team went on to show that antibodies that target ACE2 could inhibit the growth of the SARS virus, adding to the evidence that this protein is critical for the virus to bind and enter the cell.

The study concludes that compounds that inhibit ACE2 in humans may prove to be effective treatments against SARS.  ACE inhibitors now used widely to treat high blood pressure and heart disease target a related enzyme and are not directly transferable to attack ACE2.  However, since much is known about ACE inhibitors, the authors hope that the identification of ACE2 as a receptor for SARS will both focus and accelerate the ongoing research for a vaccine and therapeutics. “If SARS returns as a threat to human health, these studies may contribute to its control,” the authors wrote in Nature.

In addition to Dr. Greenough, the other UMMS scientists who co-authored the paper are Mohan Somasundaran, PhD, Katherine Ruiz de Luzuriaga, MD, and John L. Sullivan, MD.

SARS, a viral respiratory illness caused by a coronavirus, was first reported in Asia in February 2003, and over the next few months spread to more than two dozen countries in North America, South America, Europe, and Asia. According to the World Health Organization, a total of 8,098 people worldwide became sick with SARS and 774 died during the outbreak of 2003. The SARS outbreak was contained, however, it is expected that the disease could re-emerge in an annual cycle similar to the common flu.

The University of Massachusetts Medical School is one of the fastest growing academic health centers in the country and has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research. The Medical School attracts more than $151 million in extramural research funding annually, 80 percent of which comes from federal funding sources. Research dollars enable UMMS scientists to explore human disease from the molecular level to large-scale clinical trials. Basic and clinical research leads to new approaches for diagnosis, treatment and prevention of disease. Visit www.umassmed.edu for additional information.

Contact: Michael Cohen or Mark Shelton  (508) 856-2000