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Jeff Cox, PhD
Host-Pathogen Interactions Responsible for M. tuberculosis Virulence
Selected Publications | Complete Publications

phone
(415) 502-4240
email
jeffery.cox@ucsf.edu
additional websites

Tetrad Graduate Program

secondary
research affiliation

Immunology
Bacterial pathogens have evolved elaborate schemes to evade, resist, or debilitate the mammalian immune system in order to survive within the host. Furthermore, disease caused by these pathogens is influenced not only by the bacterium but also by the host's immune response. We are interested in understanding the molecular details of the relationship between host and pathogen that are responsible for tuberculosis (TB), the leading cause of death worldwide due to infectious disease. To begin to ask questions about TB pathogenesis, we have taken a molecular genetic approach to identify virulence genes of Mycobacterium tuberculosis, the causative agent of TB. Initial results suggest that M. tuberculosis employs a number of unique mechanisms that make it a highly virulent and persistent pathogen.

In accordance with its aerosol route of transmission, M. tuberculosis has evolved a marked tropism for growth in lung tissue. Using a powerful genetic screen for attenuated M. tuberculosis mutants, we have isolated a number of strains that are avirulent in the lungs of infected mice but fully virulent in other organs. Many of these mutants are defective in the production or secretion of an unusual polyketide, termed PDIM, which is found only in virulent mycobacteria. Our current research focuses on how PDIM interacts with host cells and how it endows lung-specificity to the microbe.

Another unique aspect of M. tuberculosis pathogenesis is the organismÕs ability to cause a latent, persistent infection that can reactivate to cause active disease years after the initial infection. Using new genetic and genomic tools, we are searching for genes that are critical for persistence in the mouse model of TB to address the question of how M. tuberculosis survives in the host during robust immune responses.

Our long-term research goals are to identify M. tuberculosis molecules important for virulence or persistence and to understand the role they play in the complex interactions between prokaryote and eukaryote. Ultimately, by understanding the details of TB pathogenesis at the molecular level, we hope to identify molecules that interfere with critical host-pathogen interactions that will aid in the discovery of new therapies to combat and eradicate this persistent infection.

Selected Publications

Raghavan S, Manzanillo P, Chan K, Dovey C, Cox JS (2008). Secretion of a DNA binding protein controls ESX-1 virulence factor export in Mycobacterium tuberculosis. Nature 7:454(7205):717-21.

Shiloh MU, Manzanillo P, & Cox JS. (2008). Mycobacterium tuberculosis senses host-derived carbon monoxide during macrophage infection. Cell Host & Microbe, 3(5), 323-30.

Jain M, Petzold CJ, Schelle MW, Leavell MD, Mougous JD, Bertozzi CR, Leary JA, Cox JS. (2007) Lipidomics reveals control of Mycobacterium tuberculosis virulence lipids via metabolic coupling. Proc Natl Acad Sci U S A 104(12), 5133-8.

Champion PAD, Stanley SA, Champion MM, Brown EJ, Cox JS. (2006) C-terminal Signal Sequence Promotes Virulence Factor Secretion in M. tuberculosis. Science 313, 1583-4.

Jain M, Cox JS. (2005) Novel interaction between Polyketide Synthase and cognate transporter suggests coupled synthesis and export of a virulence lipid in Mycobacterium tuberculosis. PLoS Pathogens. Sep;1(1):e2. Epub 2005 Sep 30.

Stanley SA, Raghavan S, Hwang WW, Cox JS. (2003). Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system. Proc Natl Acad Sci U S A 100, 13001-13006.

Converse SE, Mougous JD, Leavell MD, Leary JA, Bertozzi CR, Cox J S. (2003). MmpL8 is required for sulfolipid-1 biosynthesis and Mycobacterium tuberculosis virulence. Proc Natl Acad Sci U S A 100, 6121-6126.

Cox JS, Chen B, McNeil M, Jacobs WR Jr. (1999).  Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice.  Nature 402, 79-83.

 

information last updated February 2009


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