Recently, a new family of IFN-gamma-induced p47 GTPases has been identified that is essential for innate immunity against intracellular pathogens. Knock-out (KO) mouse studies have shown that three of these proteins (LRG-47, IGTP, and IRG-47) are critical for resistance to multiple category A, B, and C biodefense priority pathogens. In particular, LRG-47, but not IGTP or IRG-47, is absolutely required for resistance to the intracellular bacteria Salmonella typhimurium, Mycobacterium tuberculosis, Listeria monocytogenes, and Francisella tularensis. In contrast, all three proteins are required for resistance to the protozoan parasite Toxoplasma gondii. The underlying mechanism for the antibacterial actions of LRG-47 is unknown. It is hypothesized here that LRG-47 regulates host resistance to intracellular bacteria by promoting IFN-gamma-induced bacterial killing in macrophages. It is further hypothesized that the protein localizes to the early endosomal compartment, where it catalyzes endosomal fusion with nascent bacteria-containing phagosomes, promoting phagosomal maturation and bacterial killing. In contrast, it is proposed that IGTP and IRG-47 localize to lysosomes and catalyze different facets of phagosomal processing. These hypotheses will be tested with the following aims:
Aim I. The subcellular mechanism that underlies the impaired ability of LRG-47 KO macrophages to elicit IFN-gamma-induced bacterial killing will be defined, by determining: (a) the precise localization of LRG-47 within endosomal compartments; (b) the kinetics of LRG-47 trafficking to S. typhimurium-containing phagosomes; and (c) the effect of LRG-47 on maturation of the phagosome maturation, including lysosomal fusion, phagosomal acidification, and trafficking of endosomal markers.
Aim II. Molecular domains of LRG-47 that determine its activity will be defined. Extensive mutational analysis and functional assays will define domains required for: (a) association with endosomes and trafficking to phagosomes; (b) endosome/phagosome fusion; (c) modulation of phagosomal maturation; and (d) bacterial killing in cultured macrophages and in vivo. Thus, this research will elucidate a mechanism that is critical for IFN-gamma- induced innate resistance to intracellular bacteria, with the ultimate goal of creating broadly effective anti-bacterial agents for biodefense.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-SSS-F (01))
Program Officer
Nasseri, M Faraz
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Rogala, Allison R; Schoenborn, Alexi A; Fee, Brian E et al. (2018) Environmental factors regulate Paneth cell phenotype and host susceptibility to intestinal inflammation in Irgm1-deficient mice. Dis Model Mech 11:
Schmidt, Elyse A; Fee, Brian E; Henry, Stanley C et al. (2017) Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages. J Biol Chem 292:4651-4662
Pilla-Moffett, Danielle; Barber, Matthew F; Taylor, Gregory A et al. (2016) Interferon-Inducible GTPases in Host Resistance, Inflammation and Disease. J Mol Biol 428:3495-513
Murray, Henry W; Mitchell-Flack, Marisa; Taylor, Gregory A et al. (2015) IFN-?-induced macrophage antileishmanial mechanisms in mice: A role for immunity-related GTPases, Irgm1 and Irgm3, in Leishmania donovani infection in the liver. Exp Parasitol 157:103-9
Guo, Jintao; McQuillan, James A; Yau, Belinda et al. (2015) IRGM3 contributes to immunopathology and is required for differentiation of antigen-specific effector CD8+ T cells in experimental cerebral malaria. Infect Immun 83:1406-17
Henry, Stanley C; Schmidt, Elyse A; Fessler, Michael B et al. (2014) Palmitoylation of the immunity related GTPase, Irgm1: impact on membrane localization and ability to promote mitochondrial fission. PLoS One 9:e95021
Springer, Helen M; Schramm, Michael; Taylor, Gregory A et al. (2013) Irgm1 (LRG-47), a regulator of cell-autonomous immunity, does not localize to mycobacterial or listerial phagosomes in IFN-?-induced mouse cells. J Immunol 191:1765-74
Liu, Bo; Gulati, Ajay S; Cantillana, Viviana et al. (2013) Irgm1-deficient mice exhibit Paneth cell abnormalities and increased susceptibility to acute intestinal inflammation. Am J Physiol Gastrointest Liver Physiol 305:G573-84
Haldar, Arun K; Saka, Hector A; Piro, Anthony S et al. (2013) IRG and GBP host resistance factors target aberrant, ""non-self"" vacuoles characterized by the missing of ""self"" IRGM proteins. PLoS Pathog 9:e1003414
Liu, Zhen; Zhang, Huifang M; Yuan, Ji et al. (2012) The immunity-related GTPase Irgm3 relieves endoplasmic reticulum stress response during coxsackievirus B3 infection via a PI3K/Akt dependent pathway. Cell Microbiol 14:133-46

Showing the most recent 10 out of 34 publications