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- Reciprocal virulence and resistance polymorphism in the relationship betweenToxoplasma gondiiand the house mousePublication . Lilue, Jingtao; Müller, Urs Benedikt; Steinfeldt, Tobias; Howard, Jonathan CVirulence in the ubiquitous intracellular protozoon Toxoplasma gondii for its natural intermediate host, the mouse, appears paradoxical from an evolutionary standpoint because death of the mouse before encystment interrupts the parasite life cycle. Virulent T. gondii strains secrete kinases and pseudokinases that inactivate the immunity-related GTPases (IRG proteins) responsible for mouse resistance to avirulent strains. Such considerations stimulated a search for IRG alleles unknown in laboratory mice that might confer resistance to virulent strains of T. gondii. We report that the mouse IRG system shows extraordinary polymorphic complexity in the wild. We describe an IRG haplotype from a wild-derived mouse strain that confers resistance against virulent parasites by interference with the virulent kinase complex. In such hosts virulent strains can encyst, hinting at an explanation for the evolution of virulence polymorphism in T. gondii. DOI:http://dx.doi.org/10.7554/eLife.01298.001.
- Identification of the Microsporidian Encephalitozoon cuniculi as a New Target of the IFNγ-Inducible IRG Resistance SystemPublication . da Fonseca Ferreira-da-Silva, Marialice; Springer-Frauenhoff, Helen Maria; Bohne, Wolfgang; Howard, Jonathan C.The IRG system of IFNγ-inducible GTPases constitutes a powerful resistance mechanism in mice against Toxoplasma gondii and two Chlamydia strains but not against many other bacteria and protozoa. Why only T. gondii and Chlamydia? We hypothesized that unusual features of the entry mechanisms and intracellular replicative niches of these two organisms, neither of which resembles a phagosome, might hint at a common principle. We examined another unicellular parasitic organism of mammals, member of an early-diverging group of Fungi, that bypasses the phagocytic mechanism when it enters the host cell: the microsporidian Encephalitozoon cuniculi. Consistent with the known susceptibility of IFNγ-deficient mice to E. cuniculi infection, we found that IFNγ treatment suppresses meront development and spore formation in mouse fibroblasts in vitro, and that this effect is mediated by IRG proteins. The process resembles that previously described in T. gondii and Chlamydia resistance. Effector (GKS subfamily) IRG proteins accumulate at the parasitophorous vacuole of E. cuniculi and the meronts are eliminated. The suppression of E. cuniculi growth by IFNγ is completely reversed in cells lacking regulatory (GMS subfamily) IRG proteins, cells that effectively lack all IRG function. In addition IFNγ-induced cells infected with E. cuniculi die by necrosis as previously shown for IFNγ-induced cells resisting T. gondii infection. Thus the IRG resistance system provides cell-autonomous immunity to specific parasites from three kingdoms of life: protozoa, bacteria and fungi. The phylogenetic divergence of the three organisms whose vacuoles are now known to be involved in IRG-mediated immunity and the non-phagosomal character of the vacuoles themselves strongly suggests that the IRG system is triggered not by the presence of specific parasite components but rather by absence of specific host components on the vacuolar membrane.
- The impact of Toxoplasma gondii on the mammalian genomePublication . Müller, Urs B; Howard, Jonathan CNobody doubts that infections have imposed specialisations on the mammalian genome. However sufficient information is usually missing to attribute a specific genomic modification to pressure from a specific pathogen. Recent studies on mechanisms of mammalian resistance against the ubiquitous protozoan parasite, Toxoplasma gondii, have shown that the small rodents presumed to be largely responsible for transmission of the parasite to its definitive host, the domestic cat, possess distinctive recognition proteins, and interferon-inducible effector proteins (IRG proteins) that limit the potential virulence of the parasite. The phylogenetic association of the recognition proteins, TLR11 and TLR12, with T. gondii resistance is weak, but there is evidence for reciprocal polymorphism between parasite virulence proteins and host IRG proteins that strongly suggests current or recent coevolution.
- The Toxoplasma gondii rhoptry protein ROP18 is an Irga6-specific kinase and regulated by the dense granule protein GRA7Publication . Hermanns, Thomas; Müller, Urs B; Könen-Waisman, Stephanie; Howard, Jonathan C; Steinfeldt, TobiasIn mice, avirulent strains (e.g. types II and III) of the protozoan parasite Toxoplasma gondii are restricted by the immunity-related GTPase (IRG) resistance system. Loading of IRG proteins onto the parasitophorous vacuolar membrane (PVM) is required for vacuolar rupture resulting in parasite clearance. In virulent strain (e.g. type I) infections, polymorphic effector proteins ROP5 and ROP18 cooperate to phosphorylate and thereby inactivate mouse IRG proteins to preserve PVM integrity. In this study, we confirmed the dense granule protein GRA7 as an additional component of the ROP5/ROP18 kinase complex and identified GRA7 association with the PVM by direct binding to ROP5. The absence of GRA7 results in reduced phosphorylation of Irga6 correlated with increased vacuolar IRG protein amounts and attenuated virulence. Earlier work identified additional IRG proteins as targets of T. gondii ROP18 kinase. We show that the only specific target of ROP18 among IRG proteins is in fact Irga6. Similarly, we demonstrate that GRA7 is strictly an Irga6-specific virulence effector. This identifies T. gondii GRA7 as a regulator for ROP18-specific inactivation of Irga6. The structural diversity of the IRG proteins implies that certain family members constitute additional specific targets for other yet unknown T. gondii virulence effectors.
- The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashionPublication . Schulte, Kathrin; Pawlowski, Nikolaus; Faelber, Katja; Fröhlich, Chris; Howard, Jonathan; Daumke, OliverThe immunity-related GTPases (IRGs) constitute a powerful cell-autonomous resistance system against several intracellular pathogens. Irga6 is a dynamin-like protein that oligomerizes at the parasitophorous vacuolar membrane (PVM) of Toxoplasma gondii leading to its vesiculation. Based on a previous biochemical analysis, it has been proposed that the GTPase domains of Irga6 dimerize in an antiparallel fashion during oligomerization.
- Loss of the interferon-γ-inducible regulatory immunity-related GTPase (IRG), Irgm1, causes activation of effector IRG proteins on lysosomes, damaging lysosomal function and predicting the dramatic susceptibility of Irgm1-deficient mice to infectionPublication . Maric-Biresev, Jelena; Hunn, Julia P.; Krut, Oleg; Helms, J. Bernd; Martens, Sascha; Howard, Jonathan C.The interferon-γ (IFN-γ)-inducible immunity-related GTPase (IRG), Irgm1, plays an essential role in restraining activation of the IRG pathogen resistance system. However, the loss of Irgm1 in mice also causes a dramatic but unexplained susceptibility phenotype upon infection with a variety of pathogens, including many not normally controlled by the IRG system. This phenotype is associated with lymphopenia, hemopoietic collapse, and death of the mouse.
- Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and CancerPublication . Currey, Nicola; Jahan, Zeenat; Caldon, C Elizabeth; Tran, Phuong N; Benthani, Fahad; De Lacavalerie, Penelope; Roden, Daniel L; Gloss, Brian S; Campos, Claudia; Bean, Elaine G; Bullman, Amanda; Reibe-Pal, Saskia; Dinger, Marcel E; Febbraio, Mark A; Clarke, Stephen J; Dahlstrom, Jane E; Kohonen-Corish, Maija R JThe early events by which inflammation promotes cancer are still not fully defined. The MCC gene is silenced by promoter methylation in colitis-associated and sporadic colon tumors, but its functional significance in precancerous lesions or polyps is not known. Here, we aimed to determine the impact of Mcc deletion on the cellular pathways and carcinogenesis associated with inflammation in the mouse proximal colon.
- Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and CancerPublication . Currey, Nicola; Jahan, Zeenat; Caldon, C. Elizabeth; Tran, Phuong N.; Benthani, Fahad; De Lacavalerie, Penelope; Roden, Daniel L.; Gloss, Brian S.; Campos, Claudia; Bean, Elaine G.; Bullman, Amanda; Reibe-Pal, Saskia; Dinger, Marcel E.; Febbraio, Mark A.; Clarke, Stephen J.; Dahlstrom, Jane E.; Kohonen-Corish, Maija R.J.The early events by which inflammation promotes cancer are still not fully defined. The MCC gene is silenced by promoter methylation in colitis-associated and sporadic colon tumors, but its functional significance in precancerous lesions or polyps is not known. Here, we aimed to determine the impact of Mcc deletion on the cellular pathways and carcinogenesis associated with inflammation in the mouse proximal colon.
- Molecular mechanism for the control of virulent Toxoplasma gondii infections in wild-derived micePublication . Murillo-León, Mateo; Müller, Urs B; Zimmermann, Ines; Singh, Shishir; Widdershooven, Pia; Campos, Cláudia; Alvarez, Catalina; Könen-Waisman, Stephanie; Lukes, Nahleen; Ruzsics, Zsolt; Howard, Jonathan C; Schwemmle, Martin; Steinfeldt, TobiasSome strains of the protozoan parasite Toxoplasma gondii (such as RH) are virulent in laboratory mice because they are not restricted by the Immunity-Related GTPase (IRG) resistance system in these mouse strains. In some wild-derived Eurasian mice (such as CIM) on the other hand, polymorphic IRG proteins inhibit the replication of such virulent T. gondii strains. Here we show that this resistance is due to direct binding of the IRG protein Irgb2-b1CIM to the T. gondii virulence effector ROP5 isoform B. The Irgb2-b1 interface of this interaction is highly polymorphic and under positive selection. South American T. gondii strains are virulent even in wild-derived Eurasian mice. We were able to demonstrate that this difference in virulence is due to polymorphic ROP5 isoforms that are not targeted by Irgb2-b1CIM, indicating co-adaptation of host cell resistance GTPases and T. gondii virulence effectors.
- Irgm2 and Gate‐16 cooperatively dampen Gram‐negative bacteria‐induced caspase‐11 responsePublication . Eren, Elif; Planès, Rémi; Bagayoko, Salimata; Bordignon, Pierre‐Jean; Chaoui, Karima; Hessel, Audrey; Santoni, Karin; Pinilla, Miriam; Lagrange, Brice; Burlet‐Schiltz, Odile; Howard, Jonathan C; Henry, Thomas; Yamamoto, Masahiro; Meunier, EtienneInflammatory caspase-11 (rodent) and caspases-4/5 (humans) detect the Gram-negative bacterial component LPS within the host cell cytosol, promoting activation of the non-canonical inflammasome. Although non-canonical inflammasome-induced pyroptosis and IL-1-related cytokine release are crucial to mount an efficient immune response against various bacteria, their unrestrained activation drives sepsis. This suggests that cellular components tightly control the threshold level of the non-canonical inflammasome in order to ensure efficient but non-deleterious inflammatory responses. Here, we show that the IFN-inducible protein Irgm2 and the ATG8 family member Gate-16 cooperatively counteract Gram-negative bacteria-induced non-canonical inflammasome activation, both in cultured macrophages and in vivo. Specifically, the Irgm2/Gate-16 axis dampens caspase-11 targeting to intracellular bacteria, which lowers caspase-11-mediated pyroptosis and cytokine release. Deficiency in Irgm2 or Gate16 induces both guanylate binding protein (GBP)-dependent and GBP-independent routes for caspase-11 targeting to intracellular bacteria. Our findings identify molecular effectors that fine-tune bacteria-activated non-canonical inflammasome responses and shed light on the understanding of the immune pathways they control.