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Images reveal how rotavirus - leading cause of diarrhea - enters cells

High-resolution images constructed by researchers at Children's Hospital Boston (CHB) and Harvard Medical School (HMS) reveal the molecular rearrangements that rotavirus the most common cause of severe, dehydrating diarrhea and vomiting in children worldwide uses to break into cells.

The work, published in the August 26th edition of Nature, is a major advance in the understanding of how viruses cause infection, and illustrates how vaccine development can be made "smarter" by probing the physical architecture of viruses and finding the minimum parts needed to prime the immune system, without having to use a whole virus to make a vaccine. The researchers are now collaborating with several other institutions to develop a vaccine based on their discoveries.

Rotavirus infects almost all children, usually between 6 months and 2 years of age, and causes gastroenteritis that is sometimes severe enough to require hospitalization. The virus kills about 440,000 children each year, mainly in developing countries. The only licensed vaccine, RotaShield, was pulled from the U.S. market in 1999 because of reported cases of intestinal intussusception (a condition causing bowel obstruction).

Led by Dr. Philip Dormitzer, a physician and structural virologist in CHB's Laboratory of Molecular Medicine, the researchers used crystallography and electron microscopy to determine the geometric structure and working parts of one of the virus's surface proteins, called VP4.

Rotavirus itself is a large, soccer ball-shaped, 20-sided particle with three layers.

"The outside layer is like a landing apparatus and is stripped off in the course of entry," explains Dormitzer, who also is an assistant professor of Pediatrics at HMS and is affiliated with HMS's Center for Molecular and Cellular Dynamics. "Its job is to get the innermost portions the genes and the replication machinery -- inside the cell."

From the outer layer project 60 "spi
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Contact: Mary-Ellen Shay
mary.shay@childrens.harvard.edu
617-355-6420
Children's Hospital Boston
25-Aug-2004


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