| Mycobacterium tuberculosis is a remarkably successful human pathogen, and the mechanisms used to manipulate the host cell and evade host defenses are poorly understood. However, there exists clear evidence that the cell wall of M. tuberculosis plays a critical role during pathogenesis. Its elaborate structure and diverse components function not only as a defensive barrier, but as a specialized delivery system for virulence factors. My work on mycobacteria details two novel secretion systems responsible for exporting virulence factors outside the bacterial cell. The first pathway, involving the MmpL8 lipid transporter, functions to synthesize and secrete a complex surface-exposed sulfated glycolipid, termed sulfolipid. In the absence of MmpL8, a partially acylated SL-1 precursor, which we term SL1278, accumulates inside the cell. Importantly, MmpL8 is strictly required for virulence in the mouse model of infection, which we attribute to the accumulation of SL1278 in vivo. The second pathway, s&barbelow;ecretion in&barbelow; m&barbelow;ycobacteria or Snm, involves an alternative protein secretion pathway, which delivers multiple effectors across the cell wall and into the extracellular milieu. Interestingly, this secretion system is conserved across numerous Gram-positive bacteria, and we show that this pathway is conserved and functional in the non-pathogenic saprophyte Mycobacterium smegmatis. Using a genetic and biochemical approach, we have uncovered four new components of the Snm secretion pathway which localize to distinct cellular compartments. These studies not only provide important details to our model of the Snm pathway, but develop a useful model system to understand the secretion pathway at a mechanistic level. |
