Rhoptry Kinase ROP16 Activates STAT3 and STAT6 Resulting in Cytokine Inhibition and Arginase-1-Dependent Growth Control

English version České info

The ROP16 kinase of Toxoplasma gondii is injected into the host cell cytosol where it activates signal transducer and activator of transcription (STAT)-3 and STAT6. Here, we generated a ROP16 deletion mutant on a Type I parasite strain background, as well as a control complementation mutant with restored ROP16 expression. We investigated the biological role of the ROP16 molecule during T. gondii infection. Infection of mouse bone marrow-derived macrophages with rop16-deleted (ΔROP16) parasites resulted in increased amounts of IL-12p40 production relative to the ROP16-positive RH parental strain. High level IL-12p40 production in ΔROP16 infection was dependent on the host cell adaptor molecule MyD88, but surprisingly was independent of any previously recognized T. gondii triggered pathway linking to MyD88 (TLR2, TLR4, TLR9, TLR11, IL-1ß and IL-18). In addition, ROP16 was found to mediate the suppressive effects of Toxoplasma on LPS-induced cytokine synthesis in macrophages and on IFN-γ-induced nitric oxide production by astrocytes and microglial cells. Furthermore, ROP16 triggered synthesis of host cell arginase-1 in a STAT6-dependent manner. In fibroblasts and macrophages, failure to induce arginase-1 by ΔROP16 tachyzoites resulted in resistance to starvation conditions of limiting arginine, an essential amino acid for replication and virulence of this parasite. ΔROP16 tachyzoites that failed to induce host cell arginase-1 displayed increased replication and dissemination during in vivo infection. We conclude that encounter between Toxoplasma ROP16 and the host cell STAT signaling cascade has pleiotropic downstream effects that act in multiple and complex ways to direct the course of infection.

Vyšlo v časopise: Rhoptry Kinase ROP16 Activates STAT3 and STAT6 Resulting in Cytokine Inhibition and Arginase-1-Dependent Growth Control. PLoS Pathog 7(9): e32767. doi:10.1371/journal.ppat.1002236
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002236

Souhrn

Zdroje

1. BhavsarAPGuttmanJAFinlayBB 2007 Manipulation of host-cell pathways by bacterial pathogens. Nature 449 827 834

2. RoyCRMocarskiES 2007 Pathogen subversion of cell-intrinsic innate immunity. Nat Immunol 8 1179 1187

3. SacksDSherA 2002 Evasion of innate immunity by parasitic protozoa. Nature Immunol 3 1041 1047

4. DubeyJP 2007 The history and life-cycle of Toxoplasma gondii. WeissLMKimK Toxoplasma gondii The model apicomplexan: Perspective and methods San Diego Academic Press 1 17

5. BierlyALShufeskyWJSukhumavasiWMorelliADenkersEY 2008 Dendritic cells expressing plasmacytoid marker PDCA-1 are Trojan horses during Toxoplasma gondii infection. J Immunol 181 8445 8491

6. ChtanovaTSchaefferMHanSJvan DoorenGGNollmannM 2008 Dynamics of Neutrophil Migration in Lymph Nodes during Infection. Immunity 29 487 496

7. CourretNDarcheSSonigoPMilonGBuzoni-GatelD 2006 CD11c and CD11b expressing mouse leukocytes transport single Toxoplasma gondii tachyzoites to the brain. Blood 107 309 316

8. PetersonELiesenfeldO 2007 Clinical disease and diagnostics. WeissLMKimK Toxoplasma gondii The model apicomplexan: Perspectives and methods Amsterdam Academic Press 81 100

9. PfaffAWLiesenfeldOCandolfiE 2007 Congenital toxoplasmosis. AjiokaJWSoldatiD Toxoplasma molecular and cellular biology Norfolk Horizon Bioscience 93 110

10. DenkersEYGazzinelliRT 1998 Regulation and function of T cell-mediated immunity during Toxoplasma gondii infection. Clin Microbiol Rev 11 569 588

11. LengJButcherBADenkersEY 2009 Dysregulation of macrophage signal transduction by Toxoplasma gondii: Past progress and recent advances. Parasite Immunol 31 717 728

12. KimLDenkersEY 2006 Toxoplasma gondii triggers Gi-dependent phosphatidylinositol 3-kinase signaling required for inhibition of host cell apoptosis. J Cell Sci 119 2119 2126

13. LengJButcherBAEganCEAbdallahDSDenkersEY 2009 Toxoplasma gondii prevents chromatin remodeling initiated by TLR-triggered macrophage activation. J Immunol 182 489 497

14. ZimmermannSMurrayPJHeegKDalpkeAH 2006 Induction of Suppressor of Cytokine Signaling-1 by Toxoplasma gondii Contributes to Immune Evasion in Macrophages by Blocking IFN-{gamma} Signaling. J Immunol 176 1840 1847

15. ButcherBAKimLJohnsonPFDenkersEY 2001 Toxoplasma gondii tachyzoites inhibit proinflammatory cytokine induction in infected macrophages by preventing nuclear translocation of the transcription factor NFkB. J Immunol 167 2193 2201

16. ShapiraSHarbOMargaritJMatrajtMHanJ 2005 Initiation and termination of NFkB signaling by the intracellular protozoan parasite Toxoplasma gondii. J Cell Sci 118 3501 3508

17. ButcherBAKimLPanopoulosAWatowichSSMurrayPJ 2005 Cutting Edge: IL-10-independent STAT3 activation by Toxoplasma gondii mediates suppression of IL-12 and TNF-a in host macrophages. J Immunol 174 3148 3152

18. SaeijJPBoyleJPCollerSTaylorSSibleyLD 2006 Polymorphic secreted kinases are key virulence factors in toxoplasmosis. Science 314 1780 1783

19. SaeijJPCollerSBoyleJPJeromeMEWhiteMW 2007 Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue. Nature 445 324 327

20. HakanssonSCharronAJSibleyLD 2001 Toxoplasma evacuoles: a two-step process of secretion and fusion forms the parasitophorous vacuole. EMBO J 20 3132 3144

21. OngYCReeseMLBoothroydJC 2010 Toxoplasma rhoptry protein 16 (ROP16) subverts host function by direct tyrosine phosphorylation of STAT6. J Biol Chem 285 28731 28740

22. YamamotoMStandleyDMTakashimaSSaigaHOkuyamaM 2009 A single polymorphic amino acid on Toxoplasma gondii kinase ROP16 determines the direct and strain-specific activation of Stat3. J Exp Med 206 2747 2760

23. MurrayPJ 2007 The JAK-STAT signaling pathway: input and output integration. J Immunol 178 2623 2629

24. FoxBARistucciaJGGigleyJPBzikDJ 2009 Efficient gene replacements in Toxoplasma gondii strains deficient for nonhomologous end joining. Eukaryot Cell 8 520 529

25. ShenYSchlessingerKZhuXMeffreEQuimbyF 2004 Essential role of STAT3 in postnatal survival and growth revealed by mice lacking STAT3 serine 727 phosphorylation. Mol Cell Biol 24 407 419

26. ReichNCLiuL 2006 Tracking STAT nuclear traffic. Nat Rev Immunol 6 602 612

27. KimLButcherBALeeCWUematsuSAkiraS 2006 Toxoplasma gondii genotype determines MyD88-dependent signaling in infected macrophages. J Immunol 177 2584 2591

28. RobbenPMMordueDGTruscottSMTakedaKAkiraS 2004 Production of IL-12 by macrophages infected with Toxoplasma gondii depends on the parasite genotype. J Immunol 172 3686 3694

29. HitzigerNDellacasaIAlbigerBBarraganA 2005 Dissemination of Toxoplasma gondii to immunoprivileged organs and role of Toll/interleukin-1 receptor signalling for host resistance assessed by in vivo bioluminescence imaging. Cell Micro 6 837 848

30. ScangaCAAlibertiJJankovicDTilloyFBennounaS 2002 Cutting edge: MyD88 is required for resistance to Toxoplasma gondii infection and regulates parasite-induced IL-12 production by dendritic cells. J Immunol 168 5997 6001

31. SukhumavasiWEganCEWarrenALTaylorGAFoxBA 2008 TLR adaptor MyD88 is essential for pathogen control during oral toxoplasma gondii infection but not adaptive immunity induced by a vaccine strain of the parasite. J Immunol 181 3464 3473

32. Debierre-GrockiegoFCamposMAAzzouzNSchmidtJBiekerU 2007 Activation of TLR2 and TLR4 by glycosylphosphatidylinositols derived from Toxoplasma gondii. J Immunol 179 1129 1137

33. Del RioLButcherBABennounaSHienySSherA 2004 Toxoplasma gondii triggers MyD88-dependent and CCL2(MCP-1) responses using distinct parasite molecules and host receptors. J Immunol 172 6954 6960

34. FoureauDMMielcarzDWMenardLCSchulthessJWertsC 2010 TLR9-dependent induction of intestinal alpha-defensins by Toxoplasma gondii. J Immunol 184 7022 7029

35. YarovinskyFZhangDAndersonJFBannenbergGLSerhanCN 2005 TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308 1626 1629

36. McKeeASDzierszinskiFBoesMRoosDSPearceEJ 2004 Functional inactivation of immature dendritic cells by the intracellular parasite Toxoplasma gondii. J immunol 173 2632 2640

37. LuderCGKAlgnerMLangCBleicherNGrossU 2003 Reduced expression of the inducible nitric oxide synthase after infection with Toxoplasma gondii facilitates parasite replication in activated murine macrophages. Internat J Parasitol 33 833 844

38. ModolellMCorralizaIMLinkFSolerGEichmannK 1995 Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by TH1 and TH2 cytokines. Eur J Immunol 25 1101 1104

39. RutschmanRLangRHesseMIhleJNWynnTA 2001 Stat6-dependent substrate depletion regulates nitric oxide production. J Immunol 166 2173 2177

40. El KasmiKCQuallsJEPesceJTSmithAMThompsonRW 2008 Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol 9 1399 1406

41. SehgalPB 2008 Paradigm shifts in the cell biology of STAT signaling. Semin Cell Dev Biol 19 329 340

42. FoxBAGigleyJPBzikDJ 2004 Toxoplasma gondii lacks the enzymes required for de novo arginine biosynthesis and arginine starvation triggers cyst formation. Int J Parasitol 34 323 331

43. SibleyLDAjiokaJW 2008 Population structure of Toxoplasma gondii: clonal expansion driven by infrequent recombination and selective sweeps. Annu Rev Microbiol 62 329 351

44. BoothroydJCGriggME 2002 Population biology of Toxoplasma gondii and its relevance to human infection: do different strains cause different disease? Curr Opin Micro 5 438 442

45. GavrilescuLCDenkersEY 2001 IFN-g overproduction and high level apoptosis are associated with high but not low virulence Toxoplasma gondii infection. J Immunol 167 902 909

46. MordueDGMonroyFLa ReginaMDinarelloCASibleyLD 2001 Acute toxoplasmosis leads to lethal overproduction of Th1 cytokines. J Immunol 167 4574 4584

47. KawaiTAkiraS 2006 TLR signaling. Cell Death Differentiat 13 816 825

48. DenkersEY 2010 Toll-like receptor initiated host defense against Toxoplasma gondii. J Biomed Biotechnol 2010 737125 737125

49. LengJButcherBAEganCEAbi AbdallahDSDenkersEY 2009 Toxoplasma gondii prevents chromatin remodeling initiated by Toll-like receptor-triggered macrophages activation. J Immunol 182 489 497

50. HeimesaatMMBereswillSFischerAFuchsDStruckD 2006 Gram-Negative Bacteria Aggravate Murine Small Intestinal Th1-Type Immunopathology following Oral Infection with Toxoplasma gondii. J Immunol 177 8785 8795

51. HeimesaatMMFischerAJahnHKNiebergallJFreudenbergM 2007 Exacerbation of Murine Ileitis By Toll-Like Receptor 4 Meditated Sensing of Lipopolysaccharide From Commensal Escherichia coli. Gut 56 941 948

52. KimSKFoutsAEBoothroydJC 2007 Toxoplasma gondii dysregulates IFN-gamma-inducible gene expression in human fibroblasts: insights from a genome-wide transcriptional profiling. J Immunol 178 5154 5165

53. LangCAlgnerMBeinertNGrossULuderCG 2006 Diverse mechanisms employed by Toxoplasma gondii to inhibit IFN-gamma-induced major histocompatibility complex class II gene expression. Microbes Infect 8 1994 2005

54. BorysiewiczEFilDKonatGW 2009 Rho proteins are negative regulators of TLR2, TLR3, and TLR4 signaling in astrocytes. J Neurosci Res 87 1565 1572

55. WilmsHSieversJRickertURostami-YazdiMMrowietzU 2010 Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-1beta, TNF-alpha and IL-6 in an in-vitro model of brain inflammation. J Neuroinflammation 7 30

56. Deckert-SchluterMBluethmannHKaeferNRangASchluterD 1999 Interferon-gamma receptor-mediated but not tumor necrosis factor receptor type 1- or type 2-mediated signaling is crucial for the activation of cerebral blood vessel endothelial cells and microglia in murine Toxoplasma encephalitis. Am J Pathol 154 1549 1561

57. Scharton-KerstenTYapGMagramJSherA 1997 Inducible nitric oxide is essential for host control of persistent but not acute infection with the intracellular pathogen Toxoplasma gondii. J Exp Med 185 1 13

58. SchluterDDeckert-SchluterMLorenzEMeyerTRollinghoffM 1999 Inhibition of inducible nitric oxide synthase exacerbates chronic cerebral toxoplasmosis in Toxoplasma gondii-susceptible C57BL/6 mice but does not reactivate the latent disease in T. gondii-resistant BALB/c mice. J Immunol 162 3512 3518

59. ModolellMChoiBSRyanROHancockMTitusRG 2009 Local suppression of T cell responses by arginase-induced L-arginine depletion in nonhealing leishmaniasis. PLoS Negl Trop Dis 3 e480

60. PesceJTRamalingamTRMentink-KaneMMWilsonMSEl KasmiKC 2009 Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog 5 e1000371

61. CandolfiEHunterCARemingtonJS 1994 Mitogen- and antigen-specific proliferation of T cells in murine toxoplasmosis is inhibited by reactive nitrogen intermediates. Infect Immun 62 1995 2001

62. HaqueSKhanIHaqueAKasperL 1994 Impairment of the cellular immune response in acute murine toxoplasmosis: Regulation of IL-2 production and macrophage-mediated inhibitory effects. Infect Immun 62 2908 2916

63. KhanIAMatsuuraTKasperLH 1996 Activation-mediated CD4+ T cell unresponsiveness during acute Toxoplasma gondii infection in mice. International Immunol 8 887 896

64. OldenburgKRVoKTMichaelisSPaddonC 1997 Recombination-mediated PCR-directed plasmid construction in vivo in yeast. Nucleic Acids Res 25 451 452

65. KimLButcherBADenkersEY 2004 Toxoplasma gondii interferes with lipopolysaccharide-induced mitogen-activated protein kinase activation by mechanisms distinct from endotoxin tolerance. J Immunol 172 3003 3010

66. BennounaSBlissSKCurielTJDenkersEY 2003 Cross-talk in the innate immune system: neutrophils instruct early recruitment and activation of dendritic cells during microbial infection. J Immunol 171 6052 6058

67. ButchiNBDuMPetersonKE 2010 Interactions between TLR7 and TLR9 agonists and receptors regulate innate immune responses by astrocytes and microglia. Glia 58 650 664

68. BurgJLGroverCMPoulettyPBoothroydJC 1989 Direct and sensitive detection of a pathogenic protozoan, Toxoplasma gondii, by polymerase chain reaction. J Clin Microbiol 27 1787 1792

69. CassaingSBessieresMHBerryABerrebiAFabreR 2006 Comparison between two amplification sets for molecular diagnosis of toxoplasmosis by real-time PCR. J Clin Microbiol 44 720 724

70. HibbsJBTaintorRVavrinZRachlinE 1988 Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Com 157 87 92