Academic Background:

Ph.D. University of California, San Francisco, CA. 2000
Damon Runyon Foundation Scholar (www.damonrunyon.org)

Pathogenesis of tuberculosis

Mycobacterium tuberculosis is often called the world's most successful pathogen. It is estimated that one third of the human population has been exposed to this organism, and tuberculosis (TB) kills millions every year. Unlike many other bacterial pathogens that cause acute disease and replicate only in a specific host niche, M. tuberculosis can maintain a chronic infection by adapting to many distinctly different host microenvironments. Our lab is focused on defining the survival strategies used by this pathogen in each of these environments.

To this end, we have developed a variety of new methodologies, which take advantage of both classical genetic tools and genome sequence information. Using these methods, we have identified hundreds of mycobacterial genes that are specifically required for the bacterium to survive under a variety of conditions including acute and chronic infection models. Current work is focused on the characterizing the functional roles played by these virulence systems.

Specific projects include:

1)Understanding how nutrients are acquired in vivo. M. tuberculosis resides largely within a membrane bound compartment during infection, and it remains unclear how the bacterium acquires nutrients in this apparently isolated niche. We have identified a series of lipid and carbohydrate import systems that are critical for growth during specific phases of disease. One of these functions as a sterol uptake system, which has lead to the discovery that host cholesterol is an essential carbon source during chronic infection (see figure). We are currently focused on defining the mechanisms by which the bacterium extracts and degrades nutrients, such as cholesterol, from the host cell and understanding why the nutritional habits of the bacterium change so dramatically as disease progresses.

RFP-labeledM. tuberculosis resides in
cholesterol rich regions of the cell (green).

2)Understanding the unique physiology of the mycobacterial cell wall. The cell envelope of M. tuberculosis forms a unique barrier to environmental insults and is essential for the viability of the pathogen. Using a combination of high-throughput genetic, biochemical and structural approaches, we are investigating how phosphosignaling cascades regulate the synthesis of this complex structure.

Cell wall synthesis (green) is dysregulated in mycobacterial mutants compared to wild type cells (red).

3)Metabolic regulation of cell growth and antibiotic sensitivity. The immune system of the host exerts a variety of stresses on the bacterium, which cause it to stop replicating and become refractory to antibiotic treatment. Using a combination of genetic and metabolomic approaches, we are defining the mechanisms by which M. tuberculosis senses these stresses and responds by reducing its growth and metabolic rate.

To see information on the Sassetti Lab .