| Mycobacterium tuberculosis (M. tb), the etiologic agent of tuberculosis, infects more than 1/3 of the global population and is the leading cause of deaths due to a single bacterium worldwide. Upon inhalation of M. tb, there are four potential outcomes of infection: (1) immediate clearance of the bacterium and no apparent disease; (2) primary disease; (3) latent infection that never reactivates; or (4) latent infection with reactivation disease months or years later. The greatest challenge in the treatment and prevention of tuberculosis is the ability of M. tb to establish a latent infection, thereby avoiding eradication by the immune system or antimicrobials. The initial interaction between M. tb and host immune defense mechanisms influences the outcome of infection. While significant progress has been made in defining the host determinants of mycobacterial disease, the bacterial determinants and the molecular basis for latency of M. tb are not well understood.; In this dissertation, the role of the mce1 operon during M. tb infection is established. We show that M. tb disrupted in the mce1 operon causes rapidly progressive disease in the murine model of infection. An mce1 mutant is hypervirulent, fails to stimulate protective granuloma formation, and does not enter a persistent infection phase in the mouse lung. In vitro, mce1 mutants are significantly reduced in their ability to stimulate cytokine, chemokine, and effector molecule production by infected macrophages, and proliferate intracellularly. Since M. tb activates macrophages through Toll-like receptors, we investigated the role of TLR2 and TLR4 in mce1-mediated macrophage activation. Mce1 mutants are significantly reduced in their ability to signal via TLR2 in vitro. A cell wall-associated lipoprotein. Mce1e, was identified as a TLR2 agonist. Thus, the failure of mce1 mutants to induce an acute innate immune response via TLR2 may account for their ability to cause rapidly progressive disease rather than persistent infection in the mouse model of tuberculosis. Determining the precise function of the mce1 genes of M. tb may lead to novel strategies for controlling latent infection. |
