Tuberculosis

More about the science

Although improvements in living standards have reduced the incidence of TB in the U.S. and other wealthy nations, the disease is on a skyrocketing ascent in impoverished regions of the world as conditions of overcrowding, poor sanitation and malnutrition proliferate.

Despite intensive investigation, many mysteries concerning tuberculosis remain. Infection begins when nasal droplets—containing tubercle bacilli no larger than 2 µm in diameter— penetrate the respiratory alveoli of the lungs. There, white blood cells known as macrophages sample the alveolar mucosa in search of foreign organisms, ingesting M. tuberculosis bacilli and enclosing them in phagosomes. Activation of these macrophages kills the enclosed mycobacteria but under the proper conditions, M. tuberculosis is able to outwit these defenses, enabling tuberculosis bacteria to grow and multiply within the phagosome.

New research seeks to uncover the means by which the pathogen survives and grows within the intracellular environment of the human macrophage. Conditions encountered there require bacteria to adapt and survive the many stresses they are subjected to. To accomplish this, tuberculosis bacilli are able to selectively express genes essential to survival and modify this expression in the presence of changing environmental cues.

A PCR-based RNA technique known as selective capture of transcribed sequences or SCOTS, developed in the Clark-Curtis lab, is helping to unlock the secrets of tubercular gene expression within the human phagosome. The strategy is capable of  identifying patterns of gene expression in small numbers of bacteria present during the natural infection process. SCOTS has allowed the first global characterizations of bacterial gene expression in naturally infected human tissues, so far identifying nine genes of involved in M. tuberculosis pathenogenisis.

Further work centers on the development of an immunization regime using the recombinant attenuated Salmonella bacterium to deliver antigens of M. tuberculosis to optimal sites within immunized individuals. Through this method, protective immune responses against the tubercle bacilli are boosted. The strategy relies on stimulation of primary or T-cell immunity. Such immunization acts to selectively expand the desired immune response to the tuberculosis antigen but not to the antigens of bacterial or viral vectors.

Concurrently, related research conducted by Shelley Haydel and her team is peering into tubercular pathogenesis at the molecular level, in particular, the role of two-component systems in mycobacterial virulence. Genetic and biochemical approaches to the molecular mechanisms of these regulatory systems are explored through both cell culture studies and animal models. Such two-component regulators have been found to occur in nearly all pathogenic bacteria and are believed to play a critical role in the survival of bacilli and the progression of TB.

The fight against lethal infectious diseases like tuberculosis has lead to an overreliance on, and misuse of, broad spectrum antibiotics, hastening the spread of new strains displaying multiple-drug resistance and exacerbating disease containment efforts, particularly in the developing world. The ability to address the worldwide threat of tuberculosis ultimately rests on our ability to detect, treat and prevent the disease through techniques grounded in a more complete understanding the disease process.

The Institute's research is making significant strides in the direction of this essential understanding, through basic investigation of infection and survival of M. tuberculosis coupled with highly innovative strategies for new vaccine development.