Pitt, Children’s Researchers Find Molecule That Could Lead to Effective Tuberculosis Vaccine

The presence of a certain molecule allows the immune system to effectively police tuberculosis of the lungs and prevent it from turning into an active and deadly infection, according to a study led by researchers at the University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh of UPMC. Their findings appeared Jan. 2 in the online version of the Journal of Clinical Investigation.

More than two billion people, or one-third of the world’s population, are infected with mycobacterium tuberculosis, the bacterium that causes tuberculosis, said senior author Shabaana A. Khader, an assistant professor of pediatrics in the Pitt School of Medicine. The infection is challenging to treat partly because the bacillus, or bacterium, is able to enter cells and linger for years without causing symptoms, a condition known as latent tuberculosis. Then—typically when the immune system is impaired owing to such other reasons as age or HIV—the infection becomes active and causes the cough, night sweats, fever, and weight loss that characterize the disease.

 “A hallmark of TB that we see on chest X-rays is the granuloma, a collection of immune cells that surround the infected lung cells,” Khader said. “But what we didn’t know was the difference between a functioning protective granuloma, as in latent TB, and a nonprotective granuloma seen in active TB patients. We aimed to find immunologic markers that could show us the status of the infection.”

 For the study, which was funded by the National Institutes of Health, the researchers studied human tuberculosis-infected cells as well animal models of the disease. They found that granulomas containing ectopic lymphoid structures, which resemble lymph nodes, are associated with effective suppression of tuberculosis—and that granulomas that don’t contain ectopic lymphoid structures are associated with active tuberculosis. They also learned that immune cells, called T cells, which have a surface marker molecule called CXCR5, were associated with the presence of ectopic lymphoid structures.

 Khader used the analogy of reporting a house break-in. If a person whose house has been robbed calls 911 but doesn’t give a specific address, the police would come to the neighborhood, but they would not know which home was invaded.

 “The presence of CXCR5 provides a specific address for the infected cells and tells the immune cells where to focus their attention to contain the problem,” she explained. “That results in the formation of ectopic lymphoid structures and the protective granuloma that keeps TB infection under control, unlike in active disease. Without CXCR5, those structures did not form and active TB was more likely.

 “The protective power of CXCR5 points us in a novel direction for future management of TB,” Khader added. “These findings have powerful implications for the development of vaccines to prevent infection.”

 Coauthors include other researchers from the University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh of UPMC; the University of Rochester Medical Center; Tulane National Primate Research Center; Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Mexico; National Institute of Psychiatry, Ramon de la Fuente, Mexico; and The American British Cowdray Medical Center, Mexico.