Awards

Babak Javid of the Harvard School of Public Health in the U.S. will explore the hypothesis that latent bacteria are metabolically active during latency. The physiology of the tuberculosis bacteria during latency is not well understood. The team will use novel genetic probes to determine whether transcription and translation occur in the population of cells that are responsible for re-activation of TB from models of latency.

Philana Ling Lin of the University of Pittsburgh in the U.S. will use imaging technologies such as PET and CT scans to study the biological mechanisms related to the reactivation of latent tuberculosis to better understand the fundamental characteristics of reactivation, as well as provide insight about new ways to induce or limit reactivation of latent tuberculosis. This project's Phase I research demonstrated that a variety of tuberculosis lesions types (with both high and low metabolic activity) are seen during latent infection and lesions with higher levels of metabolic activity were more likely to reactivate under immune suppression. In Phase II, Lin will study how these lesions evolve during early infection to determine what factors may be responsible for the development of active disease and latent infection.

Maria Lerm of Linkoping University in Sweden will test her hypothesis that TB latency is a dynamic process in which a portion of the bacilli, when ingested by macrophages, trigger a genetic program where bacteria cycle between active and latent phases. Understanding whether this dynamic cycle exists could give new insights into maintaining or targeting the latent bacteria, which is the major reservoir of TB globally.

Kyu Rhee of Weill Cornell Medical College in the U.S. will test the theory that the tuberculosis (TB) bacterium uses protein-based structures termed metabolosomes to enter into, maintain, and exit from latency or non-replication. Understanding how metabolosomes work will aid in development of drugs that target TB. This project's Phase I research demonstrated that latent or non-replicating M. tuberculosis undergo a metabolic remodeling that is accompanied by the reversible formation of enzyme-based metabolosomes. In Phase II, Rhee and colleagues will characterize and determine how essential these metabolosomes are to entering and exiting latency or non-replication, which could help identify them as targets for new drug therapies for TB.

Because adult stem cells reside in a microenvironment that maintains an inactive metabolic state, Bikul Das of Stanford University in the U.S. will examine whether TB hijacks this niche to maintain latency.

Sarah Fortune of Harvard University will research whether chromatin crystallization, in which DNA condenses into a protective matrix due to environmental stress, occurs in tuberculosis and is a characteristic of latent organisms.

Matyas Sandor of the University of Wisconsin will graft granulomas, nodules that form as a result of long-term inflammation, to study the role they play in TB latency and reactivation.

Alexandre Alcais of French National Institute for Health and Medical Research will study whether there is a genetic basis for innate resistance to TB infection through genome-wide linkage analysis of TB-specific T-cell phenotypes.

Pulmonary macrophages are the principal host of tuberculosis, where it can remain latent and inaccessible to current TB drug therapies. Dmitry Shayakhmetov of the University of Washington will study whether infecting these host cells with adenovirus will induce rapid cell death, reducing TB load and blocking the re-infection cycle.

Amelia Crampin of the London School of Hygiene & Tropical Medicine will study a group of people found to have latent tuberculosis in the 1980s to test her hypothesis that a measurable portion of them have cleared the infection spontaneously. Proof that some people can clear infection opens the door for research to discover how this works.