Researchers Find Molecule That Polices TB Lung Infection

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

More than 2 billion people or one-third of the world's population are infected with mycobacterium tuberculosis, the bacterium that causes TB, says senior author Shabaana A. Khader, PhD, assistant professor of pediatrics, Pitt School of Medicine. The infection is challenging to treat partly because the bacillus is able to enter cells and linger for years without causing symptoms, known as latent TB. Then, typically when the immune system becomes impaired due to other reasons such 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 says. "But what we didn't know was the difference between a functioning protective granulomae, as in latent TB, and a non-protective 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 TB-infected cells as well animal models of the disease. They found that granulomas that contain ectopic lymphoid structures, which resemble lymph nodes, are associated with effective suppression of TB, and that granulomas that don't contain them are associated with active TB. They also learned that immune cells called T cells that had a surface marker molecule called CXCR5 were associated with the presence of ectopic lymphoid structures.

It's akin to reporting a break-in, Khader says. If a person calls 911 because of a robbery, but doesn't give a specific address, the immune system police could come to the neighborhood but don't know for certain which home was invaded.

"The presence of CXCR5 provides a specific address for the infected cells that tells the immune cells where to focus their attention to contain the problem," she explains. "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."

When the researchers delivered CXCR5 T cells from donor animals to TB-infected mice that lacked CXCR5, T cell localization and ectopic lymphoid structure formation was restored, leading to decreased susceptibility to TB.

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

Co-authors 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.

The study was funded NIH grants AI083541, HL105427, RR026006, AI091457, RR020159, RR000164, HL69409, AI060422, and AI91036 as well as Children's Hospital of Pittsburgh of UPMC.

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