http://hdl.handle.net/10400.7/280 2020-03-07T13:53:15Z 2020-03-07T13:53:15Z Maric-Biresev, Jelena Hunn, Julia P. Krut, Oleg Helms, J. Bernd Martens, Sascha Howard, Jonathan C. http://hdl.handle.net/10400.7/581 2016-04-27T02:00:41Z 2016-04-20T00:00:00Z

Título: 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 infection Autor: Maric-Biresev, Jelena; Hunn, Julia P.; Krut, Oleg; Helms, J. Bernd; Martens, Sascha; Howard, Jonathan C. Resumo: 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.

2016-04-20T00:00:00Z Schulte, Kathrin Pawlowski, Nikolaus Faelber, Katja Fröhlich, Chris Howard, Jonathan Daumke, Oliver http://hdl.handle.net/10400.7/555 2016-03-08T03:00:16Z 2016-03-02T00:00:00Z

Título: The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion Autor: Schulte, Kathrin; Pawlowski, Nikolaus; Faelber, Katja; Fröhlich, Chris; Howard, Jonathan; Daumke, Oliver Resumo: The 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.

2016-03-02T00:00:00Z Lilue, Jingtao Müller, Urs Benedikt Steinfeldt, Tobias Howard, Jonathan C http://hdl.handle.net/10400.7/456 2015-10-31T03:00:23Z 2013-01-01T00:00:00Z

Título: Reciprocal virulence and resistance polymorphism in the relationship betweenToxoplasma gondiiand the house mouse Autor: Lilue, Jingtao; Müller, Urs Benedikt; Steinfeldt, Tobias; Howard, Jonathan C Resumo: Virulence 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.

2013-01-01T00:00:00Z da Fonseca Ferreira-da-Silva, Marialice Springer-Frauenhoff, Helen Maria Bohne, Wolfgang Howard, Jonathan C. http://hdl.handle.net/10400.7/342 2015-10-06T02:00:30Z 2014-10-30T00:00:00Z

Título: Identification of the Microsporidian Encephalitozoon cuniculi as a New Target of the IFNγ-Inducible IRG Resistance System Autor: da Fonseca Ferreira-da-Silva, Marialice; Springer-Frauenhoff, Helen Maria; Bohne, Wolfgang; Howard, Jonathan C. Resumo: 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.

2014-10-30T00:00:00Z