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• W2076287192 abstract "To promote their survival, intracellular pathogens must confront microbicidal activities induced by interferons. In this issue of Cell Host & Microbe, Fentress et al. show that Toxoplasma gondii evades intracellular killing by deploying a virulence determinant, ROP18, which acts by directly phosphorylating and disabling an IFN-γ-inducible immunity-related GTPase involved in pathogen clearance. To promote their survival, intracellular pathogens must confront microbicidal activities induced by interferons. In this issue of Cell Host & Microbe, Fentress et al. show that Toxoplasma gondii evades intracellular killing by deploying a virulence determinant, ROP18, which acts by directly phosphorylating and disabling an IFN-γ-inducible immunity-related GTPase involved in pathogen clearance. Toxoplasma gondii is an obligate intracellular parasite. Upon infection, the pathogen resides in parasitophorous vacuoles of host cells. The majority of Toxoplasma isolates belong to one of three distinct clonal lineages, types I, II, and III. In immunocompetent mice, the three types of T. gondii display significant differences in virulence, with type I being hypervirulent and type II and III strains avirulent. The molecular basis for this strain-specific difference in the behavior of T. gondii isolates is a hotly pursued area of investigation. Host resistance against T. gondii requires the generation of T helper 1 lymphocytes that produce IFN-γ, a cytokine essential for cellular activation and parasite killing. IFN-γ induces a large group of microbicidal molecules that includes nitric oxide and an interesting family of 47 kDa immunity-related GTPases (IRGs). Experiments with knockout animals have indicated that the latter proteins possess a broad range of antimicrobial and regulatory functions that play a critical role in host defense against a variety of intracellular bacterial and parasitic pathogens (Hunn et al., 2010Hunn J.P. Feng C.G. Sher A. Howard J.C. Mamm. Genome. 2010; (in press. Published online October 30, 2010)https://doi.org/10.1007/s00335-010-9293-3Crossref PubMed Scopus (79) Google Scholar). Irgm1 and Irgm3, the two best-studied members of the IRG family, have previously been shown to be required for resistance to T. gondii infection in vivo as well as IFN-γ-dependent restriction of parasite replication in macrophages (Hunn et al., 2010Hunn J.P. Feng C.G. Sher A. Howard J.C. Mamm. Genome. 2010; (in press. Published online October 30, 2010)https://doi.org/10.1007/s00335-010-9293-3Crossref PubMed Scopus (79) Google Scholar). Infection with avirulent strains of Toxoplasma in vitro is associated with the rapid trafficking and recruitment of multiple IRGs to the membrane of the vacuoles in which the parasite resides, with Irgb6 and Irgb10 being the most prominent IRG proteins recruited (Khaminets et al., 2010Khaminets A. Hunn J.P. Könen-Waisman S. Zhao Y.O. Preukschat D. Coers J. Boyle J.P. Ong Y.C. Boothroyd J.C. Reichmann G. Howard J.C. Cell. Microbiol. 2010; 12: 939-961Crossref PubMed Scopus (131) Google Scholar, Zhao et al., 2009Zhao Y. Ferguson D.J. Wilson D.C. Howard J.C. Sibley L.D. Yap G.S. J. Immunol. 2009; 182: 3775-3781Crossref PubMed Scopus (105) Google Scholar). Interestingly, when virulent type I Toxoplasma strains were used for infection in the same system, the loading to the parasitophorous vacuoles of IRG proteins and in particular Irgb6 was found to be significantly reduced, suggesting a role for this process in parasite virulence. In recent years, there have been major breakthroughs utilizing elegant genetic approaches to decipher the molecular basis of virulence in T. gondii (Saeij et al., 2006Saeij J.P. Boyle J.P. Coller S. Taylor S. Sibley L.D. Brooke-Powell E.T. Ajioka J.W. Boothroyd J.C. Science. 2006; 314: 1780-1783Crossref PubMed Scopus (397) Google Scholar, Saeij et al., 2007Saeij J.P. Coller S. Boyle J.P. Jerome M.E. White M.W. Boothroyd J.C. Nature. 2007; 445: 324-327Crossref PubMed Scopus (406) Google Scholar, Taylor et al., 2006Taylor S. Barragan A. Su C. Fux B. Fentress S.J. Tang K. Beatty W.L. Hajj H.E. Jerome M. Behnke M.S. et al.Science. 2006; 314: 1776-1780Crossref PubMed Scopus (381) Google Scholar). These studies involving genetic crosses between parasite strains with different virulence phenotypes have revealed a major role for the Toxoplasma rhoptry proteins (ROPs), ROP18 and ROP16, in virulence determination. Rhoptries are secretory organelles that discharge their contents during parasite invasion of host cells. The ROPs released during this process can enter the cytosol and, in the case of ROP16, transit to the nucleus. In previous studies, ROP16 was found to regulate expression of host genes involved in macrophage activation through its phosphorylation of STAT3 and STAT6 (Saeij et al., 2007Saeij J.P. Coller S. Boyle J.P. Jerome M.E. White M.W. Boothroyd J.C. Nature. 2007; 445: 324-327Crossref PubMed Scopus (406) Google Scholar, Yamamoto et al., 2009Yamamoto M. Standley D.M. Takashima S. Saiga H. Okuyama M. Kayama H. Kubo E. Ito H. Takaura M. Matsuda T. et al.J. Exp. Med. 2009; 206: 2747-2760Crossref PubMed Scopus (167) Google Scholar). An article in this issue of Cell Host & Microbe now reveals a second parasite immune evasion strategy employed by virulent T. gondii strains involving the phosphorylation by ROP18 of Irgb6, an IRG protein with a previously undefined role in host defense (Fentress et al., 2010Fentress S.J. Behnke M.S. Dunay I.R. Mashayekhi M. Rommereim L.M. Fox B.A. Bzik D.J. Taylor G.A. Turk B.E. Lichti C.F. et al.Cell Host Microbe. 2010; 8 (this issue): 484-495Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar). ROP18 is a highly polymorphic serine-threonine kinase. After release into the cytosol of host cells, ROP18 is targeted to the parasitophorous vacuole membrane (Håkansson et al., 2001Håkansson S. Charron A.J. Sibley L.D. EMBO J. 2001; 20: 3132-3144Crossref PubMed Scopus (222) Google Scholar). Transgenic expression of ROP18 from a type I strain in a type III strain that is normally avirulent led to a significant increase in virulence during mouse infection (Taylor et al., 2006Taylor S. Barragan A. Su C. Fux B. Fentress S.J. Tang K. Beatty W.L. Hajj H.E. Jerome M. Behnke M.S. et al.Science. 2006; 314: 1776-1780Crossref PubMed Scopus (381) Google Scholar). Although the function of ROP18 is not fully understood, it has been shown to phosphorylate parasitic substrates, and overexpression of the kinase results in an increase in the rate of intravacuolar parasite replication in vitro (El Hajj et al., 2007El Hajj H. Lebrun M. Arold S.T. Vial H. Labesse G. Dubremetz J.F. PLoS Pathog. 2007; 3: e14Crossref PubMed Scopus (143) Google Scholar). In the current study reported in Cell Host and Microbe, Fentress et al., 2010Fentress S.J. Behnke M.S. Dunay I.R. Mashayekhi M. Rommereim L.M. Fox B.A. Bzik D.J. Taylor G.A. Turk B.E. Lichti C.F. et al.Cell Host Microbe. 2010; 8 (this issue): 484-495Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar demonstrate that ROP18 from a type I strain phosphorylates Irgb6, thereby inhibiting the recruitment of the GTPase to parasite vacuoles, resulting in impaired parasite clearance. Although inactivation of the GTPase by phosphorylation of Irgb6 was not formally demonstrated, the authors nevertheless speculate that this process may represent a novel mechanism by which virulent type I parasites resist killing by IFN-γ-inducible GTPases. The findings reported by Fentress et al. are consistent with previous observations that infection with virulent type I T. gondii strains is associated with impaired recruitment of IRGs to parasite vacuoles and that IRG proteins protect cells against avirulent but not virulent Toxoplasma strains (Khaminets et al., 2010Khaminets A. Hunn J.P. Könen-Waisman S. Zhao Y.O. Preukschat D. Coers J. Boyle J.P. Ong Y.C. Boothroyd J.C. Reichmann G. Howard J.C. Cell. Microbiol. 2010; 12: 939-961Crossref PubMed Scopus (131) Google Scholar, Zhao et al., 2009Zhao Y. Ferguson D.J. Wilson D.C. Howard J.C. Sibley L.D. Yap G.S. J. Immunol. 2009; 182: 3775-3781Crossref PubMed Scopus (105) Google Scholar). However, in contrast to the current study, a direct role for ROP18 in inhibiting the recruitment of IRGs to Toxoplasma vacuoles was not apparent in the previous publications examining this question (Khaminets et al., 2010Khaminets A. Hunn J.P. Könen-Waisman S. Zhao Y.O. Preukschat D. Coers J. Boyle J.P. Ong Y.C. Boothroyd J.C. Reichmann G. Howard J.C. Cell. Microbiol. 2010; 12: 939-961Crossref PubMed Scopus (131) Google Scholar, Zhao et al., 2009Zhao Y. Ferguson D.J. Wilson D.C. Howard J.C. Sibley L.D. Yap G.S. J. Immunol. 2009; 182: 3775-3781Crossref PubMed Scopus (105) Google Scholar). The exact reasons for the discrepancy are unclear. Regardless, the current findings raise several fascinating questions. What is the relative contribution of individual IRGs, as well as nitric oxide, in the overall mechanism of parasite killing in IFN-γ-activated macrophages? Why is the defect in parasite killing resulting from the silencing of Irgb6 not compensated for by IFN-γ-induced Irgm1 or Irgm3? In addition, because Irgms and other IRGs share the conserved region of Irgb6 targeted by ROP18, why are these GTPases not inactivated by ROP18 by the same mechanism? In this regard, the current and a recent study have reported that ROP18 is indeed also able to phosphorylate Irga6 and Irgb10 (Steinfeldt et al., 2010Steinfeldt T. Könen-Waisman S. Tong L. Pawlowski N. Lamkemeyer T. Sibley L.D. Hunn J.P. Howard J.C. PLoS Biol. 2010; (in press)https://doi.org/10.1371/journal.pbio.1000576Crossref PubMed Scopus (171) Google Scholar). A further question concerns whether RPO18 is sufficient and acts as the sole determinant of virulence among the diverse range of T. gondii strains and whether other strain-specific kinases expressed in non-type I lineages play a related role. Interestingly, the remarkable difference in the virulence among the three major types of Toxoplasma in mice does not appear to be recapitulated in humans. Moreover, the host targets of ROP18 in mice, Irga6, Irgb6, and Irgb10, are absent in human cells (Hunn et al., 2010Hunn J.P. Feng C.G. Sher A. Howard J.C. Mamm. Genome. 2010; (in press. Published online October 30, 2010)https://doi.org/10.1007/s00335-010-9293-3Crossref PubMed Scopus (79) Google Scholar), suggesting that this parasite virulence factor may have coevolved with the IRG family. Thus, it appears that ROP18 is utilized by Toxoplasma to specifically counteract the effector functions of the IRG family, one of the most powerful host mechanisms for defense against intracellular pathogens documented in nonprimate mammalian species. This research was supported in part by the Intramural Research Program of the NIH, NIAID. Phosphorylation of Immunity-Related GTPases by a Toxoplasma gondii-Secreted Kinase Promotes Macrophage Survival and VirulenceFentress et al.Cell Host & MicrobeDecember 16, 2010In BriefMacrophages are specialized to detect and destroy intracellular microbes and yet a number of pathogens have evolved to exploit this hostile niche. Here we demonstrate that the obligate intracellular parasite Toxoplasma gondii disarms macrophage innate clearance mechanisms by secreting a serine threonine kinase called ROP18, which binds to and phosphorylates immunity-related GTPases (IRGs). Substrate profiling of ROP18 revealed a preference for a conserved motif within switch region I of the GTPase domain, a modification predicted to disrupt IRG function. Full-Text PDF Open Archive" @default.
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• W2076287192 title "Parasites Paralyze Cellular Host Defense System to Promote Virulence" @default.
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