UC Berkeley

Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis, is a highly successful pathogen that establishes a persistent human infection. The hallmark of human host response to M.tb infection is the formation of a conglomeration of immune cells called a granuloma that is thought to limit bacterial replication and spread. M.tb is able to persist within this harsh environment. Research from our laboratory demonstrates a role for a 13-gene cluster called the mce1 operon in immune modulation within this environment that allows the bacilli to persist. We hypothesize that fluctuations in expression of the mce1 operon during the course of infection are involved in the stable maintenance of the granuloma, which is also protective for the mycobacteria.

A mce1 operon mutant strain of M.tb ( dmce1 ) is hypervirulent in a mouse model of infection. Infected mice are unable to mount a proper granulomatous response. In vitro studies with RAW macrophages and A549 epithelial cells infected with dmce1 demonstrate that this is likely due to an aberrant early innate immune response. In this dissertation we used primary mouse bone marrow derived macrophages and dendritic cells to further corroborate these findings. We found that macrophage and dendritic cell cytokine and chemokine production was impaired in response to infection with dmce1 , and dendritic cells failed to upregulate costimulatory molecules that are essential for their role in linking the innate and adaptive immune responses. The cell envelope of dmce1 was shown previously to contain an accumulation of mycolic acids that are not present in wild-type M.tb. We also investigated whether M.tb alters its lipid profile to directly or indirectly modulate the immune response. Our data show that the accumulated lipids from dmce1 do not block TLR2 signaling, nor do they directly inhibit macrophage or dendritic cell activation. Instead, these lipids may alter the bacterial cell wall architecture in such a way as to induce other, yet uncharacterized innate immune signaling pathway. These observations, nevertheless, show that early events in the interaction of M.tb with host immune cells have dramatic consequences later, and ultimately determine the clinical fate of this interaction — persistence or active disease.