Receptor findings reveal how rotavirus causes diarrhea
By Ruth SoRelle, M.P.H.
More than a decade after Mary Estes, Ph.D., of Baylor College of Medicine in Houston and her colleagues discovered the NSP4, the first known protein toxin released by an intestinal pathogen, they have identified the receptor that gives the poison entry to intestinal cells and elucidated much of the way in which it causes diarrhea.
Cellular receptor
By identifying the cellular receptor on intestinal cells, they now have a better understanding the mechanism through which the enterotoxin interacts to cause diarrhea.
"We knew that identifying the receptor might not be straightforward," said Estes, professor of molecular virology and microbiology at BCM. In a report in the Proceedings of the National Academy of Sciences, Estes and her colleagues describe two receptors for the enterotoxin, both of them integrins. (The report is considered inaugural because it is the first that Estes has published in the journal since her election to the National Academy of Sciences.)
The two, integrin alpha1 beta1 and integrin alpha2 beta1, are members of a class of molecules that are involved in attaching cells to other cells and to the extracellular matrix (a part of tissue that is not part of any cell). Integrins also are involved in transforming or translating cell signals.
Better understanding of enterotoxin
In looking for the receptor, Estes and her colleagues also learned more about the enterotoxin itself.
"It's a new ligand for binding to integrins," she said. "It begins to give us an understanding of how the enterotoxin works in the intestine. Two different domains of the enterotoxin are involved in this interaction. One domain is for binding and the other domain is for signaling through the receptor." (A ligand is a specific molecule that binds a chemical or another molecule to a particular site.)
She said she hopes to study the signaling aspect of the enterotoxin more closely because it could hold the clue to the mechanism of induction of diarrheal disease.
"There may be ways to block the interaction between the enterotoxin and the receptor to treat diarrheal disease," said Estes, who is also director of the Texas Medical Center Digestive Diseases Center.
Common cause of diarrhea
Rotavirus is one of the most common causes of diarrhea, resulting in approximately 3 million cases of diarrhea and 55,000 hospitalizations for diarrhea and dehydration in children under the age of five each year in the United States alone. Worldwide, it causes nearly half a million deaths each year.
Finding out how rotavirus causes diarrhea and looking for ways to block it is a major aim of Estes' research.
Others who took part in this work include Carl Q.-Y. Zeng, Joseph M. Hyser, Budi Utama and Sue E. Crawford of BCM, Neung-Seon Seo, Kate J. Kim and Magnus Höök of Texas A&M University Health Science Center at Houston.
Funding for this work came from the National Institutes of Health, including a grant that funds the Texas Medical Center Digestive Diseases Center.
The paper is available at http://www.pnas.org/cgi/reprint/0803934105v1.
