Transcriptional Analysis of Murine Macrophages Infected with Different Strains Identifies Novel Regulation of Host Signaling Pathways

English version České info

Most isolates of Toxoplasma from Europe and North America fall into one of three genetically distinct clonal lineages, the type I, II and III lineages. However, in South America these strains are rarely isolated and instead a great variety of other strains are found. T. gondii strains differ widely in a number of phenotypes in mice, such as virulence, persistence, oral infectivity, migratory capacity, induction of cytokine expression and modulation of host gene expression. The outcome of toxoplasmosis in patients is also variable and we hypothesize that, besides host and environmental factors, the genotype of the parasite strain plays a major role. The molecular basis for these differences in pathogenesis, especially in strains other than the clonal lineages, remains largely unexplored. Macrophages play an essential role in the early immune response against T. gondii and are also the cell type preferentially infected in vivo. To determine if non-canonical Toxoplasma strains have unique interactions with the host cell, we infected murine macrophages with 29 different Toxoplasma strains, representing global diversity, and used RNA-sequencing to determine host and parasite transcriptomes. We identified large differences between strains in the expression level of known parasite effectors and large chromosomal structural variation in some strains. We also identified novel strain-specifically regulated host pathways, including the regulation of the type I interferon response by some atypical strains. IFNβ production by infected cells was associated with parasite killing, independent of interferon gamma activation, and dependent on endosomal Toll-like receptors in macrophages and the cytoplasmic receptor retinoic acid-inducible gene 1 (RIG-I) in fibroblasts.

Vyšlo v časopise: Transcriptional Analysis of Murine Macrophages Infected with Different Strains Identifies Novel Regulation of Host Signaling Pathways. PLoS Pathog 9(12): e32767. doi:10.1371/journal.ppat.1003779
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003779

Souhrn

Zdroje

1. DubremetzJF (1998) Host cell invasion by Toxoplasma gondii. Trends Microbiol 6 : 27–30.

2. HoffmannS, BatzMB, MorrisJGJr (2012) Annual cost of illness and quality-adjusted life year losses in the United States due to 14 foodborne pathogens. J Food Prot 75 : 1292–1302.

3. WalkerM, ZuntJR (2005) Parasitic central nervous system infections in immunocompromised hosts. Clin Infect Dis 40 : 1005–1015.

4. GilbertRE, FreemanK, LagoEG, Bahia-OliveiraLMG, TanHK, et al. (2008) Ocular sequelae of congenital toxoplasmosis in Brazil compared with Europe. PLoS Negl Trop Dis 2: e277.

5. JamiesonSE, Peixoto-RangelAL, HargraveAC, RoubaixL-Ad, MuiEJ, et al. (2010) Evidence for associations between the purinergic receptor P2X(7) (P2RX7) and toxoplasmosis. Genes Immun 11 : 374–383.

6. WitolaWH, MuiE, HargraveA, LiuS, HypoliteM, et al. (2011) NALP1 influences susceptibility to human congenital toxoplasmosis, proinflammatory cytokine response, and fate of Toxoplasma gondii-infected monocytic cells. Infect Immun 79 : 756–766.

7. BelaSR, DutraMS, MuiE, MontpetitA, OliveiraFS, et al. (2012) Impaired innate immunity in mice deficient in interleukin-1 receptor-associated kinase 4 leads to defective type 1 T cell responses, B cell expansion, and enhanced susceptibility to infection with Toxoplasma gondii. Infect Immun 80 : 4298–4308.

8. MeloMB, JensenKD, SaeijJP (2011) Toxoplasma gondii effectors are master regulators of the inflammatory response. Trends Parasitol 27 : 487–495.

9. McLeodR, BoyerKM, LeeD, MuiE, WroblewskiK, et al. (2012) Prematurity and severity are associated with Toxoplasma gondii alleles (NCCCTS, 1981–2009). Clin Infect Dis 54 : 1595–1605.

10. SibleyLD, BoothroydJC (1992) Virulent strains of Toxoplasma gondii comprise a single clonal lineage. Nature 359 : 82–85.

11. KhanA, DubeyJP, SuC, AjiokaJW, RosenthalBM, et al. (2011) Genetic analyses of atypical Toxoplasma gondii strains reveal a fourth clonal lineage in North America. Int J Parasitol 41 : 645–655.

12. DardéM-L (2004) Genetic analysis of the diversity in Toxoplasma gondii. Ann Ist Super Sanita 40 : 57–63.

13. KhanA, JordanC, MuccioliC, VallochiAL, RizzoLV, et al. (2006) Genetic divergence of Toxoplasma gondii strains associated with ocular toxoplasmosis, Brazil. Emerg Infect Dis 12 : 942–949.

14. PenaHFJ, GennariSM, DubeyJP, SuC (2008) Population structure and mouse-virulence of Toxoplasma gondii in Brazil. Int J Parasitol 38 : 561–569.

15. SuC, KhanA, ZhouP, MajumdarD, AjzenbergD, et al. (2012) Globally diverse Toxoplasma gondii isolates comprise six major clades originating from a small number of distinct ancestral lineages. Proc Natl Acad Sci USA 109 : 5844–5849.

16. KhanA, MillerN, RoosDS, DubeyJP, AjzenbergD, et al. (2011) A monomorphic haplotype of chromosome Ia is associated with widespread success in clonal and nonclonal populations of Toxoplasma gondii. mBio 2: e00228–00211.

17. KhanA, FuxB, SuC, DubeyJP, DardeML, et al. (2007) Recent transcontinental sweep of Toxoplasma gondii driven by a single monomorphic chromosome. Proc Natl Acad Sci USA 104 : 14872–14877.

18. MinotS, MeloMB, LiF, LuD, NiedelmanW, et al. (2012) Admixture and recombination among Toxoplasma gondii lineages explain global genome diversity. Proc Natl Acad Sci USA 109 : 13458–13463.

19. KhanA, TaylorS, AjiokaJW, RosenthalBM, SibleyLD (2009) Selection at a single locus leads to widespread expansion of Toxoplasma gondii lineages that are virulent in mice. PLoS Genet 5: e1000404.

20. SaeijJPJ, BoyleJP, CollerS, TaylorS, SibleyLD, et al. (2006) Polymorphic secreted kinases are key virulence factors in toxoplasmosis. Science 314 : 1780–1783.

21. DubeyJP, LindsayDS, SpeerCA (1998) Structures of Toxoplasma gondii tachyzoites, bradyzoites, and sporozoites and biology and development of tissue cysts. Clin Microbiol Rev 11 : 267–299.

22. SaeijJPJ, CollerS, BoyleJP, JeromeME, WhiteMW, et al. (2007) Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue. Nature 445 : 324–327.

23. BehnkeMS, KhanA, WoottonJC, DubeyJP, TangK, et al. (2011) Virulence differences in Toxoplasma mediated by amplification of a family of polymorphic pseudokinases. Proc Natl Acad Sci USA 108 : 9631–9636.

24. ReeseML, ZeinerGM, SaeijJP, BoothroydJC, BoyleJP (2011) Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulence. Proc Natl Acad Sci USA 108 : 9625–9630.

25. TaylorS, BarraganA, SuC, FuxB, FentressSJ, et al. (2006) A secreted serine-threonine kinase determines virulence in the eukaryotic pathogen Toxoplasma gondii. Science 314 : 1776–1780.

26. FentressSJ, BehnkeMS, DunayIR, MashayekhiM, RommereimLM, et al. (2010) Phosphorylation of Immunity-Related GTPases by a Toxoplasma gondii-Secreted Kinase Promotes Macrophage Survival and Virulence. Cell Host Microbe 8 : 484–495.

27. SteinfeldtT, Konen-WaismanS, TongL, PawlowskiN, LamkemeyerT, et al. (2010) Phosphorylation of mouse immunity-related GTPase (IRG) resistance proteins is an evasion strategy for virulent Toxoplasma gondii. PLoS Biol 8: e1000576.

28. NiedelmanW, GoldDA, RosowskiEE, SprokholtJK, LimD, et al. (2012) The rhoptry proteins ROP18 and ROP5 mediate Toxoplasma gondii evasion of the murine, but not the human, interferon-gamma response. PLoS Pathog 8: e1002784.

29. BehnkeMS, FentressSJ, MashayekhiM, LiLX, TaylorGA, et al. (2012) The Polymorphic Pseudokinase ROP5 Controls Virulence in Toxoplasma gondii by Regulating the Active Kinase ROP18. PLoS Pathog 8: e1002992.

30. MartensS, ParvanovaI, ZerrahnJ, GriffithsG, SchellG, et al. (2005) Disruption of Toxoplasma gondii parasitophorous vacuoles by the mouse p47-resistance GTPases. PLoS Pathog 1: e24.

31. RosowskiEE, SaeijJP (2012) Toxoplasma gondii Clonal Strains All Inhibit STAT1 Transcriptional Activity but Polymorphic Effectors Differentially Modulate IFNgamma Induced Gene Expression and STAT1 Phosphorylation. PLoS ONE 7: e51448.

32. RosowskiEE, LuD, JulienL, RoddaL, GaiserRA, et al. (2011) Strain-specific activation of the NF-kappaB pathway by GRA15, a novel Toxoplasma gondii dense granule protein. J Exp Med 208 : 195–212.

33. PeixotoL, ChenF, HarbOS, DavisPH, BeitingDP, et al. (2010) Integrative Genomic Approaches Highlight a Family of Parasite-Specific Kinases that Regulate Host Responses. Cell Host Microbe 8 : 208–218.

34. OngYC, BoyleJP, BoothroydJC (2011) Strain-dependent host transcriptional responses to Toxoplasma infection are largely conserved in mammalian and avian hosts. PLoS ONE 6: e26369.

35. AjzenbergD (2012) High burden of congenital toxoplasmosis in the United States: the strain hypothesis? Clin Infect Dis 54 : 1606–1607.

36. GriggME, GanatraJ, BoothroydJC, MargolisTP (2001) Unusual abundance of atypical strains associated with human ocular toxoplasmosis. J Infect Dis 184 : 633–639.

37. AjzenbergD (2011) Unresolved questions about the most successful known parasite. Expert Rev Anti Infect Ther 9 : 169–171.

38. DemarM, HommelD, DjossouF, PeneauC, BoukhariR, et al. (2012) Acute toxoplasmoses in immunocompetent patients hospitalized in an intensive care unit in French Guiana. Clin Microbiol Infect 18: E221–231.

39. CarmeB, DemarM, AjzenbergD, DardeML (2009) Severe acquired toxoplasmosis caused by wild cycle of Toxoplasma gondii, French Guiana. Emerg Infect Dis 15 : 656–658.

40. GrohM, FaussartA, VillenaI, AjzenbergD, CarmeB, et al. (2012) Acute lung, heart, liver, and pancreatic involvements with hyponatremia and retinochoroiditis in a 33-year-old French Guianan patient. PLoS Negl Trop Dis 6: e1802.

41. DardéML, VillenaI, PinonJM, BeguinotI (1998) Severe toxoplasmosis caused by a Toxoplasma gondii strain with a new isoenzyme type acquired in French Guyana. J Clin Microbiol 36 : 324.

42. RadkeJR, DonaldRG, EibsA, JeromeME, BehnkeMS, et al. (2006) Changes in the expression of human cell division autoantigen-1 influence Toxoplasma gondii growth and development. PLoS Pathog 2: e105.

43. SegalE, FriedmanN, KollerD, RegevA (2004) A module map showing conditional activity of expression modules in cancer. Nat Genet 36 : 1090–1098.

44. BehnkeMS, WoottonJC, LehmannMM, RadkeJB, LucasO, et al. (2010) Coordinated progression through two subtranscriptomes underlies the tachyzoite cycle of Toxoplasma gondii. PLoS ONE 5: e12354.

45. JensenKD, WangY, WojnoED, ShastriAJ, HuK, et al. (2011) Toxoplasma polymorphic effectors determine macrophage polarization and intestinal inflammation. Cell Host Microbe 9 : 472–483.

46. YamamotoM, StandleyD, TakashimaS, SaigaH, OkuyamaM, et al. (2009) A single polymorphic amino acid on Toxoplasma gondii kinase ROP16 determines the direct and strain-specific activation of Stat3. J Exp Med

47. OngY-C, ReeseML, BoothroydJC (2010) Toxoplasma Rhoptry Protein 16 (ROP16) Subverts Host Function by Direct Tyrosine Phosphorylation of STAT6. J Biol Chem 285 : 28731–28740.

48. TakeuchiO, AkiraS (2009) Innate immunity to virus infection. Immunol Rev 227 : 75–86.

49. SuAI, CookeMP, ChingKA, HakakY, WalkerJR, et al. (2002) Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci USA 99 : 4465–4470.

50. SaeijJP, BoyleJP, BoothroydJC (2005) Differences among the three major strains of Toxoplasma gondii and their specific interactions with the infected host. Trends Parasitol 21 : 476–481.

51. ElmoreSA, JonesJL, ConradPA, PattonS, LindsayDS, et al. (2010) Toxoplasma gondii: epidemiology, feline clinical aspects, and prevention. Trends Parasitol 26 : 190–196.

52. SergentV, CautainB, KhalifeJ, DesléeD, BastienP, et al. (2005) Innate refractoriness of the Lewis rat to toxoplasmosis is a dominant trait that is intrinsic to bone marrow-derived cells. Infect Immun 73 : 6990–6997.

53. HuberJP, FarrarJD (2011) Regulation of effector and memory T-cell functions by type I interferon. Immunology 132 : 466–474.

54. MacMickingJD (2012) Interferon-inducible effector mechanisms in cell-autonomous immunity. Nat Rev Immunol 12 : 367–382.

55. CostaVM, TorresKC, MendoncaRZ, GresserI, GollobKJ, et al. (2006) Type I IFNs stimulate nitric oxide production and resistance to Trypanosoma cruzi infection. J Immunol 177 : 3193–3200.

56. KogaR, HamanoS, KuwataH, AtarashiK, OgawaM, et al. (2006) TLR-dependent induction of IFN-beta mediates host defense against Trypanosoma cruzi. J Immunol 177 : 7059–7066.

57. MattnerJ, Wandersee-SteinhauserA, PahlA, RollinghoffM, MajeauGR, et al. (2004) Protection against progressive leishmaniasis by IFN-beta. J Immunol 172 : 7574–7582.

58. MorrellCN, SrivastavaK, SwaimA, LeeMT, ChenJ, et al. (2011) Beta interferon suppresses the development of experimental cerebral malaria. Infect Immun 79 : 1750–1758.

59. VigarioAM, BelnoueE, GrunerAC, MauduitM, KayibandaM, et al. (2007) Recombinant human IFN-alpha inhibits cerebral malaria and reduces parasite burden in mice. J Immunol 178 : 6416–6425.

60. PichyangkulS, YongvanitchitK, Kum-arbU, HemmiH, AkiraS, et al. (2004) Malaria blood stage parasites activate human plasmacytoid dendritic cells and murine dendritic cells through a Toll-like receptor 9-dependent pathway. J Immunol 172 : 4926–4933.

61. ChesslerAD, CaradonnaKL, Da'daraA, BurleighBA (2011) Type I interferons increase host susceptibility to Trypanosoma cruzi infection. Infect Immun 79 : 2112–2119.

62. KhouriR, BaficaA, Silva MdaP, NoronhaA, KolbJP, et al. (2009) IFN-beta impairs superoxide-dependent parasite killing in human macrophages: evidence for a deleterious role of SOD1 in cutaneous leishmaniasis. J Immunol 182 : 2525–2531.

63. SharmaS, DeOliveiraRB, KalantariP, ParrocheP, GoutagnyN, et al. (2011) Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome. Immunity 35 : 194–207.

64. HaqueA, BestSE, AmmerdorfferA, DesbarrieresL, de OcaMM, et al. (2011) Type I interferons suppress CD4(+) T-cell-dependent parasite control during blood-stage Plasmodium infection. Eur J Immunol 41 : 2688–2698.

65. TeijaroJR, NgC, LeeAM, SullivanBM, SheehanKC, et al. (2013) Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science 340 : 207–211.

66. WilsonEB, YamadaDH, ElsaesserH, HerskovitzJ, DengJ, et al. (2013) Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science 340 : 202–207.

67. WangY, SwieckiM, CellaM, AlberG, SchreiberRD, et al. (2012) Timing and magnitude of type I interferon responses by distinct sensors impact CD8 T cell exhaustion and chronic viral infection. Cell Host Microbe 11 : 631–642.

68. OrellanaMA, SuzukiY, AraujoF, RemingtonJS (1991) Role of beta interferon in resistance to Toxoplasma gondii infection. Infect Immun 59 : 3287–3290.

69. SchmitzJL, CarlinJM, BordenEC, ByrneGI (1989) Beta interferon inhibits Toxoplasma gondii growth in human monocyte-derived macrophages. Infect Immun 57 : 3254–3256.

70. MinnsLA, MenardLC, FoureauDM, DarcheS, RonetC, et al. (2006) TLR9 is required for the gut-associated lymphoid tissue response following oral infection of Toxoplasma gondii. J Immunol 176 : 7589–7597.

71. FoureauDM, MielcarzDW, MenardLC, SchulthessJ, WertsC, et al. (2010) TLR9-dependent induction of intestinal alpha-defensins by Toxoplasma gondii. J Immunol 184 : 7022–7029.

72. TelesRM, GraeberTG, KrutzikSR, MontoyaD, SchenkM, et al. (2013) Type I interferon suppresses type II interferon-triggered human anti-mycobacterial responses. Science 339 : 1448–1453.

73. Ferreira da Silva MdaF, BarbosaHS, GrossU, LuderCG (2008) Stress-related and spontaneous stage differentiation of Toxoplasma gondii. Mol Biosyst 4 : 824–834.

74. JonesTC, BienzKA, ErbP (1986) In vitro cultivation of Toxoplasma gondii cysts in astrocytes in the presence of gamma interferon. Infect Immun 51 : 147–156.

75. BougdourA, DurandauE, Brenier-PinchartMP, OrtetP, BarakatM, et al. (2013) Host cell subversion by Toxoplasma GRA16, an exported dense granule protein that targets the host cell nucleus and alters gene expression. Cell Host Microbe 13 : 489–500.

76. BrunetJ, PfaffAW, AbidiA, UnokiM, NakamuraY, et al. (2008) Toxoplasma gondii exploits UHRF1 and induces host cell cycle arrest at G2 to enable its proliferation. Cell Microbiol 10 : 908–920.

77. MolestinaRE, El-GuendyN, SinaiAP (2008) Infection with Toxoplasma gondii results in dysregulation of the host cell cycle. Cell Microbiol 10 : 1153–1165.

78. AustinP, McCullochE, TillJ (1971) Characterization of the factor in L-cell conditioned medium capable of stimulating colony formation by mouse marrow cells in culture. J Cell Physiol 77 : 121–134.

79. TrapnellC, RobertsA, GoffL, PerteaG, KimD, et al. (2012) Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc 7 : 562–578.

80. GoteaV, OvcharenkoI (2008) DiRE: identifying distant regulatory elements of co-expressed genes. Nucleic Acids Res 36: W133–139.

81. SubramanianA, TamayoP, MoothaVK, MukherjeeS, EbertBL, et al. (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102 : 15545–15550.

82. RobertsZJ, GoutagnyN, PereraPY, KatoH, KumarH, et al. (2007) The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis. J Exp Med 204 : 1559–1569.

83. Korber B (2000) HIV Signature and sequence variation analysis. . In: Rodrigo AG, Learn GH, editors. Computational analysis of HIV molecular sequences. Dordrecht, Netherlands: Kluwer Academic Publishers. pp. 55–72.