RESUMO
The original version of this Article contained an error in the Acknowledgements, which incorrectly omitted the following: 'C.C., C.A., and J.C.H. were supported by the Fundação Calouste Gulbenkian through a grant from the Instituto Gulbenkian de Ciência and by the research infrastructure Congento, project LISBOA-01-0145-FEDER-022170, co-financed by Lisboa Regional Operational Programme (Lisboa 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and Foundation for Science and Technology (Portugal).' This has been corrected in both the PDF and HTML versions of the Article.
RESUMO
Some 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.
Assuntos
GTP Fosfo-Hidrolases/imunologia , Interações Hospedeiro-Parasita/imunologia , Proteínas de Protozoários/imunologia , Toxoplasma/patogenicidade , Toxoplasmose Animal/imunologia , Animais , Resistência à Doença/genética , Resistência à Doença/imunologia , Feminino , Fibroblastos , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Células HEK293 , Interações Hospedeiro-Parasita/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Isoformas de Proteínas , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Seleção Genética/imunologia , Toxoplasma/imunologia , Toxoplasmose Animal/parasitologia , Virulência/imunologiaRESUMO
Nobody 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.
Assuntos
Interações Hospedeiro-Patógeno/imunologia , Receptores Toll-Like/imunologia , Toxoplasma/imunologia , Toxoplasma/patogenicidade , Toxoplasmose/patologia , Animais , Gatos , Genoma/genética , Interações Hospedeiro-Patógeno/genética , Humanos , Hidroliases/genética , Camundongos , Receptores Toll-Like/genética , Toxoplasma/genética , Toxoplasmose/parasitologia , Virulência/genéticaRESUMO
In 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.