CUMC researchers develop first true mouse model of typhoid infection

Published on October 26, 2012 at 2:18 AM · No Comments

Columbia University Medical Center (CUMC) researchers have created the first true mouse model of typhoid infection. The development promises to advance the study of typhoid and the creation of new vaccines against the infection, which remains a major health threat in developing countries. The paper was published today in the online edition of the journal Cell.

"Vaccines are the most practical solution for preventing typhoid in the Third World. Unfortunately, existing typhoid vaccines are only modestly effective, leaving millions of people vulnerable to infection. With our new mouse model, the first of its kind, we have a powerful tool for investigating the disease and devising better vaccine strategies," said study co-leader Sankar Ghosh, PhD, the Silverstein and Hutt Family Professor and chair of microbiology & immunology at CUMC.

Typhoid is caused by the bacterium Salmonella typhi, which is spread through contaminated drinking water or food. While typhoid is rare in the United States, it is a common health problem in the developing world, affecting more than 2 million people each year and leading to 200,000 deaths. Symptoms of typhoid infection include high fever, fatigue, stomach pains, headache, and loss of appetite. Typhoid can be treated with antibiotics. Without therapy, the illness may last up to a month, with a fatality rate between 12 and 30 percent. There are two typhoid vaccines, with efficacy rates ranging from 50 to 80 percent.

Since mice and other laboratory animals are resistant to S. typhi, it has been difficult to develop and test new vaccination approaches. In the current experiment, Dr. Ghosh and his colleagues sought to determine why mice cannot be infected with S. typhi, with the ultimate goal of creating an animal model for studying the disease.

Evidence suggested that toll-like receptors (TLRs), which are expressed on the surface of key immune cells such as macrophages and dendritic cells, might be involved. Such cells are part of the innate immune response, the body's first-line defense against infectious microbes. For various reasons, the researchers zeroed in on a particular TLR: TLR11. One, this receptor is expressed all over the gastrointestinal lining, or epithelium, where S. typhi infection begins, and two, the receptor is found in mice, but not in humans. Also, in an earlier study, the CUMC team found that TLR11 protects mice infected with the Toxoplasma gondii, the parasite that causes toxoplasmosis in humans.

To determine whether TLR11 protects mice against S. typhi, Dr. Ghosh created a strain of mice that lack the receptor. When the TLR11 "knockout" mice were challenged with orally administered S. typhi, they developed typhoid-like symptoms. Next, the researchers demonstrated that the mice could be successfully immunized against S. typhi with a heat-killed vaccine.

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