Mechanisms of Macrophage Detection and Control of Mycobacterium tuberculosis Infection

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2016-04-15

Authors

Collins, Angela Christine

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Abstract

Macrophages use different mechanisms to recognize and respond to Mycobacterium tuberculosis infection. Macrophage recognition of M. tuberculosis is characterized by the production of a robust type I interferon response dependent on the activation of a cytosolic surveillance pathway by the recognition of M. tuberculosis DNA in the cytosol. The DNA sensor recognizing M. tuberculosis DNA and initiating activation of the cytosolic surveillance pathway has yet to be defined. Here we describe a role for the recently characterized DNA sensor cGAS in the detection of M. tuberculosis infection and initiation of the type I interferon response as well as a role for cGAS in the targeting of M. tuberculosis to the autophagosome. We demonstrate that cGAS deficiency is associated with decreased survival in a mouse model of M. tuberculosis infection. The second part of this thesis explores how macrophages respond to M. tuberculosis infection. We previously showed that in mice M. tuberculosis infection induces the expression of the carbon monoxide producing enzyme heme oxygenase (HO1) in the macrophage and that the CO is sensed by M. tuberculosis to initiate a dormancy program. Mice deficient in HO1 succumb to M. tuberculosis infection more readily than wild-type (WT) mice. While the mechanisms used by mouse macrophages to control intracellular M. tuberculosis infection, including nitric oxide synthase, the respiratory burst, acidification and HO1 are well studied, how human macrophages control M. tuberculosis infection is less well understood. Here we show that HO1 is induced by and colocalizes with M. tuberculosis in both mouse and human tuberculosis lesions, and that M. tuberculosis induces and colocalizes with HO1 during human macrophage infection in vitro. HO1 enzymatic activity in human macrophages is necessary for inflammatory cytokine production and for control of intracellular M. tuberculosis replication. Finally, we find that a polymorphism in the HO1 promoter is associated with susceptibility to human tuberculosis. Thus, we demonstrate an important role for HO1 in controlling human tuberculosis.

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