Christopher Sassetti, Ph.D.

Academic Role: Assistant Professor

Faculty Appointment(s) In:
   Molecular Genetics and Microbiology

Other Affiliation(s):
   Center for AIDS Research

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 growth in 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-labeled M. tuberculosis resides in
cholesterol rich regions of the cell (green).

2) Understanding how the bacterium adapts to the intracellular environment.   We have identified a regulon that is dramatically induced at the pH of the mycobacterial phagosome.  Many of these genes are involved in modification of the complex cell envelope of the bacterium, suggesting that this structure is altered upon phagocytosis.  We are currently investigating the regulatory system that controls these genes and the physiological effects of their induction.

3) Defining metabolic adaptations to hypoxia.  Oxygen limitation induces a state of "nonreplicating persistence" in M. tuberculosis that mimic the some aspects of the metabolic state of the bacterium in hypoxic TB lesions; the bacteria stop replicating, become refractory to antibiotic treatment, and persist for very long periods without a loss of viability.  We have identified two classes of bacterial mutants in which this response is altered.  One class is unable to survive under these conditions, and the second fail to arrest their replication.  By characterizing the corresponding genes, we hope to understand how M. tuberculosis regulates its growth rate and persists in human TB lesions.

Publications

Sassetti, C.M. and  Rubin, E.J.^.   The open book of infectious diseases.  Nature Medicine. 13: 279-280. (2007)

Joshi, S. M., Pandey, A.K., Capite, N., Fortune, S.M., Rubin, E.J., and Sassetti, C.M.  Characterization of mycobacterial virulence genes through genetic interaction mapping. Proc. Nat. Acad. Sci.  103:11760-11765. (2006).

Fortune S.M, Jaeger A., Chase M.R, Sarracino, D.A, Sassetti C.M, Sherman D.R., Bloom B.R. and Rubin E.J. Mutually-dependent secretion of proteins required for mycobacterial virulence. Proc. Nat. Acad. Sci.  102:10676-81. (2005).

Rengarajan,J., Sassetti, C. M., Naroditskaya^, V., Sloutsky^, A., Bloom^, B.R. and Rubin, E. J.^.   The folate pathway is a target for resistance to the drug para-aminosalicylic acid (PAS) in mycobacteria. Molecular Microbiology 53:275-282 (2004)

Sassetti, C. M. and Rubin, E. J.  Genetic requirements for mycobacterial survival during infection.  Proc. Nat. Acad. Sci. 100:12989-12994 (2003)

Sassetti, C. M., Boyd, D. H. and Rubin, E. J. Genes required for mycobacterial growth defined by high density mutagenesis.  Molecular Microbiology. 48: 77-84.  (2003)

Sassetti, C. M., Boyd, D. H. and Rubin, E. J. Comprehensive identification of conditionally essential genes in mycobacteria. Proc. Nat. Acad. Sci. 98: 12712-12717. (2001)

Rotation Projects

We have identified a number of bacterial pathways that are specifically required for growth during infection, whose functions can be used to infer different aspects of the host environment.  We are particularly interested in:

1. Transmembrane transport systems that are involved in either nutrient acquisition or the export of bacterial products into the host cell.
   
2. Transcriptional regulators that are required for adaptation to the host environment.
   
3. Metabolic genes that provide information on the nutrients available to the bacterium

A variety of genetic, biochemical, and informatic methods will be used to define the functions of these genes and the role played by each during infection.

Current lab members:

Academic Background:

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

Other:

Howard Hughes Medical Institute Investigator (www.hhmi.org)

Office: S6 141
Phone: 508 856 3678
E-mail: Christopher.Sassetti@umassmed.edu
Keywords: Microbial Pathogenesis, Genomics, Tuberculosis, Infectious Disease, Genetics

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