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Typhoid collects on gallstones to perpetuate disease

Posted on | March 3, 2010 | 1,539 views |

New study finds a sugar-based biofilm gives protection to the bacteria that causes typhoid fever

A new study suggests that the bacteria that cause typhoid fever collect in tiny but persistent communities on gallstones, making the infection particularly hard to fight in so-called “carriers” — people who have the disease but show no symptoms.

Humans who harbor these bacterial communities in their gallbladders, even without symptoms, are able to infect others with active typhoid fever, especially in developing areas of the world with poor sanitation. The disease is transmitted through fecal-oral contact, such as through poor hand-washing by people who prepare food.

Typhoid fever is rare in the United States, but it affects an estimated 22 million people worldwide, causing symptoms that include a high fever, headache, weakness and fatigue, and abdominal pain. It leads to hundreds of thousands of deaths each year.

Scientists and physicians have known for decades that these bacteria, Salmonella enterica serovar Typhi, accumulate in the gallbladder. In fact, the most widely accepted treatment of chronic typhoid infection is removal of the gallbladder.

“We’re trying to get to the heart of why this is. Why does Salmonella sit in a pool of highly concentrated detergent, which is what bile is, but not die?” said John Gunn, professor of molecular virology, immunology and medical genetics at Ohio State and senior author of the study. “It’s got to survive in some way, and a good way to survive is by forming a biofilm.”

Biofilms — in this case, the collection of bacteria on gallstones — typically do not respond well to antibiotics or the human immune response. But now that the biofilms themselves have been discovered in association with asymptomatic typhoid infection, they present a potential treatment alternative to expensive and invasive gallbladder removal, Gunn said.

Specifically, targeting a sugar polymer on the bacterial surface that promotes development of the biofilm might be a strategy to prevent biofilm formation in the first place, he said.

The research appeared in the online early edition of the Proceedings of the National Academy of Sciences.

Gunn and colleagues observed this biofilm formation in mice infected with a strain of Salmonella bacteria similar to the strain that causes typhoid fever in humans. The scientists also detected these biofilms on gallstones in about
5 percent of humans in a Mexican hospital who had their gallbladders removed because of complications from gallstones. Typhoid fever is widespread in Mexico.

“The mouse data coupled with the human data suggest strongly that biofilms lay a foundation that allows for establishment and maintenance of chronic typhoid infection,” said Gunn, also a vice director of Ohio State’s Center for Microbial Interface Biology.

The researchers fed mice either normal food or a high-cholesterol diet for eight weeks, intending to induce gallstones in the animals on the fatty diet. The scientists then gave these mice a type of Salmonella bacteria designed to mimic a chronic human typhoid infection without causing actual illness in the mice. A control group of mice received no bacteria.

The number of bacteria harbored in the gallbladders of mice with gallstones increased over time, becoming abundant within 21 days, and was significantly higher than bacteria in mice that did not have any stones. No bacteria were detected in mice that weren’t given the infection.

Three weeks after infection, biofilms covered about 50 percent of the surfaces of the gallstones removed from the infected mice.

“What we think is that having gallstones makes you more susceptible to becoming a carrier because it provides that environment for Salmonella to bind to the surface, form a biofilm and establish infection,” Gunn said. “Whether that happens 100 percent of the time, nobody knows.”

In a second component of the mouse study, the researchers tested fresh fecal pellets from infected mice to test the association between gallstone biofilms and transmission of a typhoid-like infection via feces, a phenomenon called “shedding.” The mice with gallstones shed three times more bacteria than did infected mice without gallstones.

The mouse data not only supported Gunn’s hypothesis that gallstones present at least one surface on which Salmonella biofilms form and maintain the carrier state of typhoid fever. The researchers also realized they had developed a new mouse model for further study of asymptomatic typhoid carriage.

This work is supported by the National Institutes of Health and a graduate education fellowship from Ohio State’s Public Health Preparedness for Infectious Diseases initiative.

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