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Outline I.	Definition Immunity related GTPases are important mediators for clearance of intracellular pathogens such as Chlamydia, Mycobacteria, Leishmania, Listeria, and Salmonella. IRGs have been demonstrated to be a host cellular target modified by obligate intracellular pathogens. IRGs in mice have been characterized to be involved in the destabilization of vacuoles that harbor pathogens. Certain strains of Toxoplasma gondii phosphorylate and inactivate IRGs to avoid the innate cellular response. In humans, IRGs have been associated with clearance of Mycobacterium tuberculosis and polymorphisms have been associated with an elevated risk for Crohn’s Disease.

a. Control of IFN-g-mediated host resistance to intracellular pathogens by immunity-related GTPases (p47 GTPases). Gregory A. et al. Microbes and Infection Volume 9, Issues 14-15, November-December 2007, Pages 1644-1651.
 * This paper also has an IRG activation flow chart***

Structure description and functional domains i.	Figure 1 and Figure 2 a.	Mouse Example of IRG structure ( from pdb) b.	Human Example of IRG Structure( predicted structure by homology modeling)

II. History a.	Phlyogenetic Analyses i.	40-50 million years ago genome disruption ii. Vertebrate/Cephalochordate Evolution 1.	Lead to variable IRGs 2.	Function maintains homologous phenotypes 3.	Can talk about the differences between vertebrates and cephalochordates but more importantly how they are similar a.	Question in point-Cephs do not have IFNg or IFNg receptors. b.	The Evolutionarily Dynamic IFN-Inducible GTPase Proteins Play Conserved Immune Functions in Vertebrates and Cephalochordates. Guang Li, Juyong Zhang, Yi Sun, Hua Wang, and Yiquan Wang iii. Mammalian 1.	Same citation as above

iv. 21 in mice v.	Truncated in Humans vi. Phylogentic Tree Figure 3

III. IRGs (Mice) Fig 4 – IRG mechanisms in mice A.	Expression and localization B.	Mechanism of Action/Specific Interactions a.	Mycobacterium, Leishmania, MCMV, etc. i.	Bashkirov PV, Akimov SA, Evseev AI, Schmid SL, Zimmerberg J et al (2008) GTPase cycle of dynamin is coupled to membrane squeeze and release, leading to spontaneous fission. Cell 135:1276–1286. ii. Carl G Feng, et al. The immunity-related GTPase Irgm1 promotes the expansion of activated CD4+ T cell populations by preventing interferon--induced cell death. Nature Immunology 9, 1279 - 1287 (2008). iii. Cell Microbiol. 2010 Jul;12(7):939-61. Epub 2010 Jan 26. Coordinated loading of IRG resistance GTPases on to the Toxoplasma gondii parasitophorous vacuole.

C.	Specific Examples of Clearance of intracellular bacteria a.	Al-Zeer MA, Al-Younes HM, Braun PR, Zerrahn J, Meyer TF (2009) IFN-gamma-inducible Irga6 mediates host resistance against Chlamydia trachomatis via autophagy. PLoS One 4:e4588 b.	Cellular & Molecular Immunology (2010) 7, 69–76; doi:10.1038/cmi.2009.100; published online 23 December 2009. IFN-inducible p47 GTPases display differential responses to Schistosoma japonicum acute infection. Xuesong Chen, Xiaotang Du, Meijuan Zhang, Donghui Zhang, Minjun Ji, and Guanling Wu.

D.	Thwarted by Tg- Paper from Cell Micro class a.	How and why i.	Cell Microbiol. 2010 Jul;12(7):939-61. Epub 2010 Jan 26. Coordinated loading of IRG resistance GTPases on to the Toxoplasma gondii parasitophorous vacuole. b.	Is it beneficial to host? Deleterious? Why?

IV. IRGM (paralog in humans) Fig5- possible mechanism of IRGs in humans A.	Where is it found and how does it function in humans? a.	Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria Sudha B. Singh, Wojciech Ornatowski, Isabelle Vergne, John Naylor, Monica Delgado, Esteban Roberts, Marisa Ponpuak, Sharon Master, Manohar Pilli, Eileen White, Masaaki Komatsu & Vojo Deretic. Nature Cell Biology 12, 1154–1165 (2010) doi:10.1038/ncb2119 b.	A synonymous IRGM B.	Is it functional or not in humans? Old school of thought. a.	Bekpen C, Hunn JP, Rohde C, Parvanova I, Guethlein L et al (2005) The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the cell autonomous resistance mechanism in the human lineage. Genome Biol 6:R92 C.	How is it different than IRGs in mice a.	Bekpen C, Marques-Bonet T, Alkan C, Antonacci F, Leogrande MB et al (2009) Death and resurrection of the human IRGM gene. PLoS Genet 5:e1000403

VI. References and further reading