Natural mutations in humans and introduced mutations in mice have unequivocally demonstrated the importance of interferon-gamma (IFN-gamma) for the control of tuberculosis (TB). How this cytokine exerts its protective effects is thought to owe much to the broad transcriptional programs it activates within Mycobacterium tuberculosis (Mto)-infected macrophages and dendritic cells. Here as many as 1,300 genes may be engaged. Prominent within this group is a new family of 47kDa guanosine 5'-triphosphatases (p47 GTPases) that confers host resistance to a number of human pathogens. At least one member of this family - LRG-47 - appears essential for combating TB in experimental mouse models. Preliminary evidence suggests that LRG-47 operates at the level of the infected cell via a mechanism distinct from all known tuberculocidal pathways, linking cytokine activation with phagolysomal fusion, events that are required for bacterial killing and which may enable Mtb antigens to be cross-presented. It is the purpose of this proposal to build on these initial observations by pursuing the following aims: (1) Characterize the intracellular location and trafficking behavior of mouse and human LRG-47 within Mtb-infected cells. Here a combination of high-resolution imaging and cell fractionation will be used to identify the LRG-47-positive compartment(s) and its recruitment to the nascent Mtb phagosome. (2) Define the molecular determinants of LRG-47 function in response to Mtb. Relocation of LRG-47 to the Mtb phagosome and subsequent remodeling of this organelle is likely to enlist other host proteins. Isolating LRG-47-interacting partners, the functional domains involved and their consequences for immunity will be dissected with an array of molecular, cellular and structural approaches. (3) Uncover Mtb-encoded pathways that counter LRG-47 - dependent immunity. Genetic screens conducted to identify bacterial components interfering with LRG-47 should yield further insights into how this GTPase operates. It could also uncover prospective drug targets. Information gleaned from these approaches will provide a paradigm for other members of the p47 GTPase family that is rapidly emerging as one of the most powerful host defense repertoires in the mammalian genome.
| Kim, Bae-Hoon; Chee, Jonathan D; Bradfield, Clinton J et al. (2016) Interferon-induced guanylate-binding proteins in inflammasome activation and host defense. Nat Immunol 17:481-9 |
| Gaudet, Ryan G; Bradfield, Clinton J; MacMicking, John D (2016) Evolution of Cell-Autonomous Effector Mechanisms in Macrophages versus Non-Immune Cells. Microbiol Spectr 4: |
| MacMicking, John D (2014) Cell-autonomous effector mechanisms against mycobacterium tuberculosis. Cold Spring Harb Perspect Med 4: |
| Das, Rituparna; Koo, Mi-Sun; Kim, Bae Hoon et al. (2013) Macrophage migration inhibitory factor (MIF) is a critical mediator of the innate immune response to Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 110:E2997-3006 |
| Randow, Felix; MacMicking, John D; James, Leo C (2013) Cellular self-defense: how cell-autonomous immunity protects against pathogens. Science 340:701-6 |
| Selleck, Elizabeth M; Fentress, Sarah J; Beatty, Wandy L et al. (2013) Guanylate-binding protein 1 (Gbp1) contributes to cell-autonomous immunity against Toxoplasma gondii. PLoS Pathog 9:e1003320 |
| MacMicking, John D (2012) Interferon-inducible effector mechanisms in cell-autonomous immunity. Nat Rev Immunol 12:367-82 |
| Shenoy, Avinash R; Wellington, David A; Kumar, Pradeep et al. (2012) GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals. Science 336:481-5 |
| Bradfield, Clinton J; Kim, Bae-Hoon; MacMicking, John D (2012) Crossing the Rubicon: new roads lead to host defense. Cell Host Microbe 11:221-3 |
| Kim, Bae-Hoon; Shenoy, Avinash R; Kumar, Pradeep et al. (2012) IFN-inducible GTPases in host cell defense. Cell Host Microbe 12:432-44 |
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