Knowledge Generation

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.

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.

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.

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.

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.

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.

With evidence that microRNA can interfere with host immune response, Qian Gao of Fudan University in China will compare microRNA expression profiles of those with active and latent TB to detect which genes which have significant differences in expression.

Jay Solnick of the University of California, Davis will explore whether the bacteria Helicobacter pylori, which can cause peptic ulcers in some people, might enhance immunity to tuberculosis and help maintain tuberculosis in a latent state.

Carl Nathan, Julien Vaubourgeix and Gang Lin of Weill Cornell Medical College will test their hypothesis that tuberculosis is able to exit latency by distributing damaged proteins to a senescent cell lineage, while more functional proteins are diverted to a lineage with full replication potential. Regulating this post-latency cell division could be the target of new drugs. This project's Phase I research demonstrated that M. tuberculosis accumulates irreversibly oxidized proteins when its replication is blocked. These proteins form small aggregates that fuse into larger ones.