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Research at Nationwide Children's: Two Proteins Could Be the Downfall of RSV Infection

931 views · Published 25 May 2012 · 1:12 · Indexed 9 October 2026

Channel: NationwideChildrens · 2012 · Science & Technology

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Using human-derived airway cells scientists can target the proteins responsible for the first two steps of RSV infection. 

The figure, made by his collaborator Dr. Will Ray, is a model of the fusion (F) protein of respiratory syncytial virus (RSV).  The model is a computer-generated model of the F protein that has allowed Dr. Peeples to visualize how it may function.  Understanding its function enough to block it in the human body might prevent hospitalization of more than 100,000 U.S. infants each year.  

Funded by the National Institutes of Health, the Cystic Fibrosis Foundation and Johnson & Johnson, Dr. Peeples leads the only lab in the world that has produced a functioning pre-triggered form of the RSV F protein in a soluble form and one of two labs using human airway cells to study RSV infection.  

"RSV has proteins unlike any other virus, which has made it very difficult to work with," said Dr. Peeples, a principal investigator in the Center for Vaccines and Immunity at The Research Institute. 

RSV is a common respiratory virus that infects the lungs and breathing passages.  Essentially all children have been infected with it by age 2.  Healthy people usually recover from RSV infection within two weeks, experiencing only mild symptoms.  However, infection can be severe in premature infants, young children and the elderly.  

RSV is the most common cause of bronchiolitis and pneumonia in children under 1 year of age. It is responsible for more hospitalizations of children than any other single cause.

RSV is an enveloped virus, meaning it is surrounded by a lipid-derived membrane that fuses with the outside membrane of a host cell, allowing the viral genome to enter the cell.  The F protein completes this fusion process, but the process begins with its companion protein on the virus surface, the glyco (G) protein.  The G protein binds to the virus receptor on host target cells. 

"The G protein is the viral navigator; it gets the virus to the right place," said Dr. Peeples. For decades, scientists have been using tumor cells to study RSV attachment.  However, Dr. Peeples found that the G protein that is so important in RSV infection in humans plays a very different role during infection of these tumor cells.  

"Tumor cells are easy to use, so we use them, but they do not reflect what happens in vivo," said Dr. Peeples. "That got us to thinking maybe there is a different receptor on the cells that line the human airway."  Now, Dr. Peeples studies G protein function using human airway epithelial cells, grown from trachea and bronchi donated for but not suitable for organ transplant. 

Dr. Peeples' lab is one of only two labs in the world using these cells to study RSV infection.  Using these cells, they are searching for the G protein receptor.  "The G protein and its receptor are major targets for vaccine and antiviral drug development," says Dr. Peeples.  "We are working to identify the receptor and to understand how it interacts with the G protein."  

After the RSV G protein attaches, the F protein takes over.  "The F protein causes the membrane of the virus to fuse with the membrane of the cell and allows the viral genome to spill into the cytoplasm of the cell," says Dr. Peeples.  "That's what really starts infection."

There are two versions of the F protein, a pre-triggered version and a triggered version.  "The pre-triggered version sits on the viral surface, wound up like a spring," said Dr. Peeples.  "It undergoes massive conformational changes when it's triggered.  It throws one arm out like a harpoon to grab the target cell then slams the viral membrane against the cell to initiate fusion."

 Dr. Peeples' lab is the only one in the world that has been able to produce the functional pre-triggered version of the F protein in a soluble form that can be studied biochemically.   

Dr. Peeples says the pre-triggered form is the most important target for blocking infection.  "If you want to make a vaccine or develop antiviral drugs, you'd want to intervene before infection begins.  You'd want the vaccine to induce antibodies that recognize the pre-triggered form of the F protein on the virus and you'd want antiviral drugs that block the triggering mechanism."

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