Browsing by Author "Steinfeldt, Tobias"
Now showing 1 - 3 of 3
Results Per Page
Sort Options
- 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.
- 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.
- 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.