Researchers describe how Norwalk virus enters intestinal cells

Nearly 30 years ago, scientists studying the Norwalk virus – a virulent intestinal bug – found that as many as 20 percent of individuals exposed to it resisted infection. Later, they determined that the resistance resulted from specific factors in their blood that determined blood type.

In a paper that appears online in the current issue of the Proceedings of the National Academy of Sciences, Dr. B. V Venkataram Prasad, professor of biochemistry and molecular biology at Baylor College of Medicine and his colleagues describe the intricate structure of the interactions between the capsid or surface protein of the Norwalk virus and the histo-blood group antigens, which determine blood type. Using X-ray crystallography, they described not only the surface protein of the virus but also the complex formed between it and the blood group antigens. The finding gives a clue about how this family of viruses has evolved and perhaps how it will change in the future.

The BCM researchers found that the histo-blood group antigens A (blood type A) and H (blood type O) bind to the capsid or surface of the virus in the same place, projecting outward from the surface of the virus.

"The orientation of these blood group antigens in the bound structure makes it appropriate that they be receptors or required molecules for entry of the virus into intestinal cells," said Prasad.

"It’s a beautiful structure," said Dr. Mary Estes, professor of molecular virology and microbiology at BCM and a co-author of the report. "It shows why this group of viruses binds to these groups of blood types and why it will not recognise others."

This finding is true for genotype 1 or the originally identified form of Norwalk virus. It is not true for genotype 2 or the form of the virus now known to be circulating on cruise ships. However, other similar mechanisms may be at play in the infection of cells by that virus as well.

"These viruses have evolved to recognise different sets of histo-blood group antigens so that they can spread out over a broader population," said Prasad. "This has not been seen, as far as we know, in other viruses."

Several years ago, studies of volunteers exposed to Norwalk showed that those who could not be infected were non-secretors, meaning that they lacked a gene for an enzyme called fucosyltransferase," said Estes. "Everyone who had the gene was susceptible to infection. Those without it did not get Norwalk."

(Secretors are people who secrete antigens revealing their blood type in other body fluids such as saliva or semen.)

"We can use this to go forward with some ideas about how to counter this virus," said Prasad. "This histo-blood group antigen binding site would be one target for making anti-viral drugs." Because there may be overlap between the areas when the different forms of Norwalk virus infect the cell, a drug that works for one type might work for both, he said.

While cruise ship infections get the most attention, the noroviruses (of which Norwalk is one) have caused major infections in hospitals, nursing homes and even at a professional football game, said graduate student Jae-Mun Choi. As the virus changes, it affects different populations.

"That is one of the reasons we have to keep tabs on this virus," he said. "It could become more virulent. It is important to be mindful of that."

Dr. Anne M. Hutson, an instructor in the department of paediatrics at BCM, whose work resulted in the identification of the secretor/non-secretor infection rate, also took part in this study.

(Source: Proceedings of the National Academy of Sciences: Baylor College of Medicine: July 2008)