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The IFN-γ-inducible GTPase, Irga6, protects mice against Toxoplasma gondii but not against Plasmodium berghei and some other intracellular pathogens.

Liesenfeld O, Parvanova I, Zerrahn J, Han SJ, Heinrich F, Muñoz M, Kaiser F, Aebischer T, Buch T, Waisman A, Reichmann G, Utermöhlen O, von Stebut E, von Loewenich FD, Bogdan C, Specht S, Saeftel M, Hoerauf A, Mota MM, Könen-Waisman S, Kaufmann SH, Howard JC - PLoS ONE (2011)

Bottom Line: The in vivo role of another member of this family, Irga6 (IIGP, IIGP1) has been studied in less detail.Susceptibility to infection with T. gondii was associated with increased mortality and reduced time to death, increased numbers of inflammatory foci in the brains and elevated parasite loads in brains of infected Irga6-deficient mice.In vitro, Irga6-deficient macrophages and fibroblasts stimulated with IFN-γ were defective in controlling parasite replication.

View Article: PubMed Central - PubMed

Affiliation: Institute of Microbiology and Hygiene, Charité Universitätsmedizin Berlin, Berlin, Germany.

ABSTRACT
Clearance of infection with intracellular pathogens in mice involves interferon-regulated GTPases of the IRG protein family. Experiments with mice genetically deficient in members of this family such as Irgm1(LRG-47), Irgm3(IGTP), and Irgd(IRG-47) has revealed a critical role in microbial clearance, especially for Toxoplasma gondii. The in vivo role of another member of this family, Irga6 (IIGP, IIGP1) has been studied in less detail. We investigated the susceptibility of two independently generated mouse strains deficient in Irga6 to in vivo infection with T. gondii, Mycobacterium tuberculosis, Leishmania mexicana, L. major, Listeria monocytogenes, Anaplasma phagocytophilum and Plasmodium berghei. Compared with wild-type mice, mice deficient in Irga6 showed increased susceptibility to oral and intraperitoneal infection with T. gondii but not to infection with the other organisms. Surprisingly, infection of Irga6-deficient mice with the related apicomplexan parasite, P. berghei, did not result in increased replication in the liver stage and no Irga6 (or any other IRG protein) was detected at the parasitophorous vacuole membrane in IFN-γ-induced wild-type cells infected with P. berghei in vitro. Susceptibility to infection with T. gondii was associated with increased mortality and reduced time to death, increased numbers of inflammatory foci in the brains and elevated parasite loads in brains of infected Irga6-deficient mice. In vitro, Irga6-deficient macrophages and fibroblasts stimulated with IFN-γ were defective in controlling parasite replication. Taken together, our results implicate Irga6 in the control of infection with T. gondii and further highlight the importance of the IRG system for resistance to this pathogen.

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Inflammatory processes following T. gondii infection in the brains of B-Irga6−/− and wild-type mice.(A) Inflammatory foci were detected histologically at 39 days after infection of B-Irga6−/− with ME49 strain T. gondii as described in Materials and Methods. (B) Cysts were counted microscopically in brain homogenates obtained from infected mice 139 days after infection, as described in Materials and Methods. (C) IFN-γ and (D) TNF were determined by ELISA in brain homogenates and serum (C only) from B-Irga6−/− mice at 29 days after infection. Means ± SD are presented from 4 individual mice; results are representative for 3 experiments performed.
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pone-0020568-g004: Inflammatory processes following T. gondii infection in the brains of B-Irga6−/− and wild-type mice.(A) Inflammatory foci were detected histologically at 39 days after infection of B-Irga6−/− with ME49 strain T. gondii as described in Materials and Methods. (B) Cysts were counted microscopically in brain homogenates obtained from infected mice 139 days after infection, as described in Materials and Methods. (C) IFN-γ and (D) TNF were determined by ELISA in brain homogenates and serum (C only) from B-Irga6−/− mice at 29 days after infection. Means ± SD are presented from 4 individual mice; results are representative for 3 experiments performed.

Mentions: To gain further insight into the increased susceptibility of Irga6−/− mice to oral infection with T. gondii, we investigated inflammatory changes and parasite loads in brains of infected wild-type and B-Irga6−/− C57BL/6 and 129/SvJ mice (Figure 4 and Figure S3). Four weeks after oral infection, the wild-type mice showed meningeal inflammation but only few inflammatory changes in the brain parenchyma compared with more pronounced meningeal and parenchymal inflammation (mostly mononuclear cells) in the Irga6−/− mice (Figure 4A). Numbers of T. gondii cysts were significantly higher in the brains of B-Irga6−/− mice compared to controls (Figure 4B). Taken together, these results suggest that mice deficient in Irga6 suffer from defective control of parasite replication resulting in increased inflammatory responses.


The IFN-γ-inducible GTPase, Irga6, protects mice against Toxoplasma gondii but not against Plasmodium berghei and some other intracellular pathogens.

Liesenfeld O, Parvanova I, Zerrahn J, Han SJ, Heinrich F, Muñoz M, Kaiser F, Aebischer T, Buch T, Waisman A, Reichmann G, Utermöhlen O, von Stebut E, von Loewenich FD, Bogdan C, Specht S, Saeftel M, Hoerauf A, Mota MM, Könen-Waisman S, Kaufmann SH, Howard JC - PLoS ONE (2011)

Inflammatory processes following T. gondii infection in the brains of B-Irga6−/− and wild-type mice.(A) Inflammatory foci were detected histologically at 39 days after infection of B-Irga6−/− with ME49 strain T. gondii as described in Materials and Methods. (B) Cysts were counted microscopically in brain homogenates obtained from infected mice 139 days after infection, as described in Materials and Methods. (C) IFN-γ and (D) TNF were determined by ELISA in brain homogenates and serum (C only) from B-Irga6−/− mice at 29 days after infection. Means ± SD are presented from 4 individual mice; results are representative for 3 experiments performed.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3117789&req=5

pone-0020568-g004: Inflammatory processes following T. gondii infection in the brains of B-Irga6−/− and wild-type mice.(A) Inflammatory foci were detected histologically at 39 days after infection of B-Irga6−/− with ME49 strain T. gondii as described in Materials and Methods. (B) Cysts were counted microscopically in brain homogenates obtained from infected mice 139 days after infection, as described in Materials and Methods. (C) IFN-γ and (D) TNF were determined by ELISA in brain homogenates and serum (C only) from B-Irga6−/− mice at 29 days after infection. Means ± SD are presented from 4 individual mice; results are representative for 3 experiments performed.
Mentions: To gain further insight into the increased susceptibility of Irga6−/− mice to oral infection with T. gondii, we investigated inflammatory changes and parasite loads in brains of infected wild-type and B-Irga6−/− C57BL/6 and 129/SvJ mice (Figure 4 and Figure S3). Four weeks after oral infection, the wild-type mice showed meningeal inflammation but only few inflammatory changes in the brain parenchyma compared with more pronounced meningeal and parenchymal inflammation (mostly mononuclear cells) in the Irga6−/− mice (Figure 4A). Numbers of T. gondii cysts were significantly higher in the brains of B-Irga6−/− mice compared to controls (Figure 4B). Taken together, these results suggest that mice deficient in Irga6 suffer from defective control of parasite replication resulting in increased inflammatory responses.

Bottom Line: The in vivo role of another member of this family, Irga6 (IIGP, IIGP1) has been studied in less detail.Susceptibility to infection with T. gondii was associated with increased mortality and reduced time to death, increased numbers of inflammatory foci in the brains and elevated parasite loads in brains of infected Irga6-deficient mice.In vitro, Irga6-deficient macrophages and fibroblasts stimulated with IFN-γ were defective in controlling parasite replication.

View Article: PubMed Central - PubMed

Affiliation: Institute of Microbiology and Hygiene, Charité Universitätsmedizin Berlin, Berlin, Germany.

ABSTRACT
Clearance of infection with intracellular pathogens in mice involves interferon-regulated GTPases of the IRG protein family. Experiments with mice genetically deficient in members of this family such as Irgm1(LRG-47), Irgm3(IGTP), and Irgd(IRG-47) has revealed a critical role in microbial clearance, especially for Toxoplasma gondii. The in vivo role of another member of this family, Irga6 (IIGP, IIGP1) has been studied in less detail. We investigated the susceptibility of two independently generated mouse strains deficient in Irga6 to in vivo infection with T. gondii, Mycobacterium tuberculosis, Leishmania mexicana, L. major, Listeria monocytogenes, Anaplasma phagocytophilum and Plasmodium berghei. Compared with wild-type mice, mice deficient in Irga6 showed increased susceptibility to oral and intraperitoneal infection with T. gondii but not to infection with the other organisms. Surprisingly, infection of Irga6-deficient mice with the related apicomplexan parasite, P. berghei, did not result in increased replication in the liver stage and no Irga6 (or any other IRG protein) was detected at the parasitophorous vacuole membrane in IFN-γ-induced wild-type cells infected with P. berghei in vitro. Susceptibility to infection with T. gondii was associated with increased mortality and reduced time to death, increased numbers of inflammatory foci in the brains and elevated parasite loads in brains of infected Irga6-deficient mice. In vitro, Irga6-deficient macrophages and fibroblasts stimulated with IFN-γ were defective in controlling parasite replication. Taken together, our results implicate Irga6 in the control of infection with T. gondii and further highlight the importance of the IRG system for resistance to this pathogen.

Show MeSH
Related in: MedlinePlus