How Rotavirus Causes Diarrhea

Rotavirus kills some 600,000 children worldwide, particularly in the developing world. Scientists have long known how the virus takes its toll: It causes the intestine to secrete copious amounts of fluid, leading to death by dehydration in vulnerable infants. Now they have figured out exactly how the pathogen opens the hydrants. In mice, the virus activates nerves that control fluid absorption and secretion in the intestine. Despite this insight, a drug that could halt the diarrhea is still a long way off.

Several kinds of infections can cause diarrhea. Toxins released by some bacteria, including one that leads to cholera and pathogenic strains of Escherichia coli, activate nerves and apparently stimulate cells of the intestinal lining to boost their water secretion. To see whether rotavirus might also be overstimulating intestinal neurons, Ove Lundgren at Göteborg University in Sweden teamed up with Lennart Svensson of the Swedish Institute for Infectious Disease Control in Solna, and several other colleagues.

The researchers applied three types of compounds known to block nerve transmission in the gut to rotavirus-infected mouse intestines kept in solution. All three compounds greatly suppressed fluid secretion, the team reports in tomorrow's Science. But the inhibitors had little, if any, effect on uninfected intestines, indicating that the rotavirus was to blame for the excessive neural activity. The researchers confirmed these observations with studies in living mice. The "simplest" explanation, says Lundgren, is that rotavirus triggers the release of chemicals in the gut that activate nerve endings beneath the intestinal lining. The activated nerves then turn on secretory reflexes in cells of the intestinal lining that discharge chloride ions into the bore of the intestine. This action is thought to draw water into the bore by osmosis.

The finding is an important milestone on the road to developing a drug against rotavirus diarrhea, says Don Powell of the University of Texas Medical Branch in Galveston. But researchers still don't know the identity of the nerve-stimulating substance released during rotavirus infection--information that would be crucial to finding candidate drugs that block the neural activity, says Helen Cooke of Ohio State Medical School in Columbus.