Children’s Hospital/Pitt-Led Team Finds Molecule That Polices TB Lung Infection, Could Lead to Effective Vaccine

PITTSBURGH, PA - January 2, 2013 - 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, said senior author Shabaana A. Khader, Ph.D., 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," Dr. Khader said. "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, Dr. Khader said. 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 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."

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," Dr. Khader said. "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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About Children's Hospital of Pittsburgh of UPMC
Renowned for its outstanding clinical services, research programs and medical education, Children's Hospital of Pittsburgh of UPMC has helped establish the standards of excellence in pediatric care. From ambulatory care to transplantation and cardiac care, talented and committed pediatric experts care for infants, children and adolescents who make more than 1 million visits to Children's and its many neighborhood locations each year. Children's also has been named consistently to several elite lists of pediatric health care facilities, including ranking 7th among children's hospitals and schools of medicine (FY 2011) in funding provided by the National Institutes of Health, and is one of 12 pediatric hospitals in the United States named to U.S. News & World Report's Honor Roll of America's "Best Children's Hospitals" for 2012–2013.

About the University of Pittsburgh School of Medicine
As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support.

Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region's economy. For more information about the School of Medicine, see www.medschool.pitt.edu.

Anita Srikameswaran, 412-578-9193, SrikamAV@upmc.edu
Andrea Kunicky, 412-692-6254, andrea.kunicky@chp.edu