Universität zu Köln

Steinfeldt, Tobias, Koenen-Waisman, Stephanie, Tong, Lan, Pawlowski, Nikolaus, Lamkemeyer, Tobias, Sibley, L. David, Hunn, Julia P. and Howard, Jonathan C. (2010). Phosphorylation of Mouse Immunity-Related GTPase (IRG) Resistance Proteins Is an Evasion Strategy for Virulent Toxoplasma gondii. PLoS. Biol., 8 (12). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1545-7885

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Abstract

Virulence of complex pathogens in mammals is generally determined by multiple components of the pathogen interacting with the functional complexity and multiple layering of the mammalian immune system. It is most unusual for the resistance of a mammalian host to be overcome by the defeat of a single defence mechanism. In this study we uncover and analyse just such a case at the molecular level, involving the widespread intracellular protozoan pathogen Toxoplasma gondii and one of its most important natural hosts, the house mouse (Mus musculus). Natural polymorphism in virulence of Eurasian T. gondii strains for mice has been correlated in genetic screens with the expression of polymorphic rhoptry kinases (ROP kinases) secreted into the host cell during infection. We show that the molecular targets of the virulent allelic form of ROP18 kinase are members of a family of cellular GTPases, the interferon-inducible IRG (immunity-related GTPase) proteins, known from earlier work to be essential resistance factors in mice against avirulent strains of T. gondii. Virulent T. gondii strain ROP18 kinase phosphorylates several mouse IRG proteins. We show that the parasite kinase phosphorylates host Irga6 at two threonines in the nucleotide-binding domain, biochemically inactivating the GTPase and inhibiting its accumulation and action at the T. gondii parasitophorous vacuole membrane. Our analysis identifies the conformationally active switch I region of the GTP-binding site as an Achilles' heel of the IRG protein pathogen-resistance mechanism. The polymorphism of ROP18 in natural T. gondii populations indicates the existence of a dynamic, rapidly evolving ecological relationship between parasite virulence factors and host resistance factors. This system should be unusually fruitful for analysis at both ecological and molecular levels since both T. gondii and the mouse are widespread and abundant in the wild and are well-established model species with excellent analytical tools available.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Steinfeldt, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Koenen-Waisman, Stephanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Tong, Lan UNSPECIFIED UNSPECIFIED UNSPECIFIED Pawlowski, Nikolaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Lamkemeyer, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Sibley, L. David UNSPECIFIED UNSPECIFIED UNSPECIFIED Hunn, Julia P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Howard, Jonathan C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-492019
DOI:	10.1371/journal.pbio.1000576
Journal or Publication Title:	PLoS. Biol.
Volume:	8
Number:	12
Date:	2010
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1545-7885
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INDOLEAMINE 2,3-DIOXYGENASE; SIGNAL-TRANSDUCTION; BINDING PROTEINS; IN-VIVO; MACROPHAGES; IIGP1; IDENTIFICATION; TRYPTOPHAN; STRAINS; DEFENSE Multiple languages Biochemistry & Molecular Biology; Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/49201