To develop new strategies to control tuberculosis (TB), a contagious disease that infects one-third of the world's population and kills almost two million people every year, the University of Pittsburgh Center for Vaccine Research has received an $11.4 million grant from the Bill & Melinda Gates Foundation. The grant will enable Pitt researchers to use new imaging technologies to study TB to shorten and simplify its course of treatment, potentially improving survival and curtailing the global TB epidemic.

"One of the most challenging issues in treating TB and stopping its spread is the length of time it takes to adequately stem the infection," said JoAnne Flynn, Ph.D., principal investigator of the grant and professor of microbiology and molecular genetics, University of Pittsburgh School of Medicine. "Current drugs are available, but we don't fully understand how or why they work. TB treatment must be continued for at least six months to be effective, placing an undue burden on those who are infected - often from the poorest and most disadvantaged countries."

According to Dr. Flynn, TB is difficult to control because the germs that cause the infection hide from the immune system in small tissue nodules called granulomas, enabling the infection to reactivate years, and even decades, later. Although for the most part TB is a curable disease, patients must adhere to treatment long after symptoms have faded. This proves challenging in many regions of the world where medication is not readily accessible. Indeed, an inadequate or incomplete course of treatment is the major factor that causes drug-resistant TB strains to develop. These strains are alarmingly high in many countries around the world.

"Current medications for TB were developed more than three decades ago," said Dr. Flynn. "To create significantly shorter and simplified approaches to treatment, we must improve our understanding of this disease and how current drugs are localized at the site of infection."

To understand more about the basic biology of TB, Dr. Flynn and colleagues are using the grant to develop positron emission tomography (PET) and computed tomography (CT) imaging studies in non-human primates. By using combined PET/CT, the researchers will be able to follow the progression of the disease in animals over time and analyze changes in tissue and responses to particular drugs. They will be using three imaging technologies - radionuclides, fluorescence and mass spectrometry - in combination to develop imaging probes and techniques to precisely locate bacteria associated with TB and to explore the underlying factors responsible for slow drug metabolism.

"By applying the tools of modern medicine to TB, we hope to lay the groundwork for real-time measurements of TB drug efficacy in clinical trials and develop new targeted therapies that will considerably shorten the length of treatment," said Dr. Flynn.

Tuberculosis is a bacterial disease usually affecting the lungs. Called pulmonary TB, the disease is characterized by a persistent cough, shortness of breath, weight loss and chest pain. Left untreated, one person with active pulmonary TB will infect on average between 10 and 15 other people every year. The bacteria associated with the disease also can infect nearly any part of the body, such as the lymph nodes, the spine or bones. TB is deadly if left untreated.

Co-investigators on the grant include Clifton Barry III, Ph.D., National Institute of Allergy and Infectious Diseases; Richard Caprioli, Ph.D., and Michelle Reyzer, Ph.D., Vanderbilt University; David Russell, Ph.D., and Warren Zipfel, Ph.D., Cornell University; Kim Janda, Ph.D., and Tobin Dickerson, Ph.D., The Scripps Research Institute; Benjamin Davis, Ph.D., Oxford University; Chet Mathis, Ph.D., Jonathan P. Carney, Ph.D., and Brian J. Lopresti, B.S., University of Pittsburgh; and Veronique Dartois, Ph.D., Novartis Institute of Tropical Disease.

The Center for Vaccine Research (CVR) at the University of Pittsburgh houses both the Regional Biocontainment Laboratory and the Vaccine Research Laboratory. Researchers at the CVR, directed by Donald S. Burke, M.D., dean of the University of Pittsburgh Graduate School of Public Health and UPMC Jonas Salk Professor of Global Health, develop new methods and strategies to prevent and treat infectious diseases, potentially improving and protecting global health.

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