Chapter 30 : Phagocyte Interactions with the Intracellular Protozoan

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in

Phagocyte Interactions with the Intracellular Protozoan , Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816650/9781555814014_Chap30-1.gif /docserver/preview/fulltext/10.1128/9781555816650/9781555814014_Chap30-2.gif


The intracellular protozoan is a pathogen of humans and an important zoonotic infection in domestic animals. The resultant toxoplasmic encephalitis, most dramatically highlighted in chronically infected AIDS patients, is lethal if not appropriately controlled by drug therapy. This chapter describes the multiple facets of early encounters between and the professional phagocytes, considering how these phagocytes lead to resistance or disease as the ultimate outcome of infection. Originally defined for their role in detection of bacterial, fungal, and viral molecules, it is now known that toll-like receptor (TLR) also possess protozoan recognition properties. The first indication for TLR-based recognition of came from the observation that MyD88-deficient mice were hypersusceptible to infection, and death was associated with defective IFN- γ and IL-12 responses. As MyD88-deficient mice uniformly succumb to during acute infection, the implication is that additional TLRs are likely important in recognition. Importantly, experiments using STAT3 macrophages show that requires this host molecule to suppress responses to LPS. For the host, it is essential to control the parasite to prevent death from infection. In the future, we can expect a major drive to determine at the molecular level how this complex balance is achieved, and indeed, this research effort is already well under way.

Citation: Denkers E. 2009. Phagocyte Interactions with the Intracellular Protozoan , p 463-476. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch30

Key Concept Ranking

Major Histocompatibility Complex Class I
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

Multiple pathways lead to IL-12 production during infection. A parasite profilin molecule triggers proinflammatory cytokine production through TLR11/MyD88 signaling. In addition, GPI molecules from the parasite surface activate both TLR2 and TLR4 for cytokine production. The TLR signaling pathways are likely to also involve p38 MAPK. The cyclophilin-18 molecule expressed by tachyzoites appears to act through the seven-transmembrane chemokine receptor CCR5 to induce dendritic cell IL-12. Finally, another pathway that does not involve MyD88, CCR5, or G-protein-mediated signaling also leads to IL-12 induction. Little is known about this last pathway except that p38 MAPK is an essential component.

Citation: Denkers E. 2009. Phagocyte Interactions with the Intracellular Protozoan , p 463-476. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch30
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2

Major phagocytic killing mechanisms operating against . (1) IFN-γ signaling through STAT1 is a major mechanism for inducing microbicidal activity. Among STAT1-inducible proteins are the IRG family members. (2) Some IRG proteins (Irgm1, Irgm3, Irga6) act to induce parasitophorous vacuole membrane breakdown and parasite elimination involving, in some cases, autophagy. (3) Independently of the IFN-γ pathway, CD40 ligation transmits signals for parasite killing that also involve autophagy. (4) Other IRG proteins (Irgd) as well as iNOS are induced by STAT1 signaling, but are only required for survival during chronic infection. How these molecules function is enigmatic.

Citation: Denkers E. 2009. Phagocyte Interactions with the Intracellular Protozoan , p 463-476. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch30
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3

mechanisms of subverting phagocyte immune function. Once inside the cell, renders cells nonresponsive to IFN-γ. This appears to occur at several levels. (1) The parasite may induce the negative regulator SOCS-1 that blocks STAT1 phosphorylation and induces its degradation. (2) There is evidence that the parasite also prevents nuclear translocation of phosphorylated STAT1, although this is less certain. (3) Some studies also suggest that may dephosphorylate STAT1 that has translocated into the nucleus in response to IFN-γ. (4) Rhoptry protein discharge during invasion; in particular, the putative serine-threonine kinase ROP16 induces STAT3 activation that downregulates proinflammatory signaling. (5) The parasite also interferes with TLR-mediated NF-κB activity in a process that may involve accelerated export from the nucleus. (6) also deactivates proinflammatory MAPK signaling cascades initiated through TLR, in a process that may involve either parasite or host phosphatase activity.

Citation: Denkers E. 2009. Phagocyte Interactions with the Intracellular Protozoan , p 463-476. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch30
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Adams, L. B.,, J. B. Hibbs, Jr.,, R. R. Taintor, and, J. L. Krahenbuhl. 1990. Microbiostatic effect of murine-activated macrophages for Toxoplasma gondii: role for synthesis of inorganic nitrogen oxides from L-arginine. J. Immunol. 144:27252729.
2. Akira, S.,, S. Uematsu, and, O. Takeuchi. 2006. Pathogen recognition and innate immunity. Cell 124:783801.
3. Alexander, J.,, and C. A. Hunter. 1998. Immunoregulation during toxoplasmosis. Chem. Immunol. 70:81102.
4. Alexander, W. S.,, and D. J. Hilton. 2004. The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Annu. Rev. Immunol. 22:503529.
5. Aliberti, J.,, D. Jankovic, and, A. Sher. 2004. Turning it on and off: regulation of dendritic cell function in Toxoplasma gondii infection. Immunol. Rev. 201:2634.
6. Aliberti, J.,, C. Reis e Sousa,, M. Schito,, S. Hieny,, T. Wells,, G. B. Huffnage, and, A. Sher. 2000. CCR5 provides a signal for microbial induced production of IL-12 by CD8α+ dendritic cells. Nat. Immunol. 1:8387.
7. Aliberti, J.,, J. G. Valenzuela,, V. B. Carruthers,, S. Hieny,, J. Andersen,, H. Charest,, C. Reis e Sousa,, A. Fairlamb,, J. M. Ribeiro, and, A. Sher. 2003. Molecular mimicry of a CCR5 binding-domain in the microbial activation of dendritic cells. Nat. Immunol. 4:485490.
8. Andrade, R. M.,, J.-M. C. Portillo,, M. Wessendarp, and, C. S. Subauste. 2005. CD40 signaling in macrophages induces activity against an intracellular pathogen independently of gamma interferon and reactive oxygen intermediates. Infect. Immun. 73:31153125.
9. Andrade, R. M.,, M. Wessendarp,, M. J. Gubbels,, B. Striepen, and, C. S. Subauste. 2006. CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. J. Clin. Investig. 116:23662377.
10. Andrade, R. M.,, M. Wessendarp, and, C. S. Subauste. 2003. CD154 activates macrophage antimicrobial activity in the absence of IFN-γ through a TNF-α-dependent mechanism. J. Immunol. 171:67506756.
11. Bafica, A.,, H. C. Santiago,, R. Goldszmid,, C. Ropert,, R. T. Gazzinelli, and, A. Sher. 2006. Cutting edge: TLR9 and TLR2 signaling together account for MyD88-dependent control of parasitemia in Trypanosoma cruzi infection. J. Immunol. 177:35153519.
12. Bennouna, S.,, S. K. Bliss,, T. J. Curiel, and, E. Y. Denkers. 2003. Cross-talk in the innate immune system: neutrophils instruct early recruitment and activation of dendritic cells during microbial infection. J. Immunol. 171:60526058.
13. Bennouna, S.,, W. Sukhumavasi, and, E. Y. Denkers. 2006. Toxoplasma gondii inhibits Toll-like receptor 4 ligand-induced mobilization of intracellular tumor necrosis factor alpha to the surface of mouse peritoneal neutrophils. Infect. Immun. 74:42744281.
14. Bliss, S. K.,, B. A. Butcher, and, E. Y. Denkers. 2000. Rapid recruitment of neutrophils with prestored IL-12 during microbial infection. J. Immunol. 165:45154521.
15. Bliss, S. K.,, L. C. Gavrilescu,, A. Alcaraz, and, E. Y. Denkers. 2001. Neutrophil depletion during Toxoplasma gondii infection leads to impaired immunity and lethal systemic pathology. Infect. Immun. 69:48984905.
16. Bliss, S. K.,, Y. Zhang, and, E. Y. Denkers. 1999. Murine neutrophil stimulation by Toxoplasma gondii antigen drives high level production of IFN-γ-independent IL-12. J. Immunol. 163:20812088.
17. Bogdan, C.,, and M. Rollinghoff. 1999. How do protozoan parasites survive inside macrophages? Parasitol. Today 15:2228.
18. Bohne, W.,, J. Heesemann, and, U. Gross. 1994. Reduced replication of Toxoplasma gondii is necessary for induction of bradyzoite-specific antigens: a possible role for nitric oxide in triggering stage conversion. Infect. Immun. 62:17611767.
19. Boothroyd, J. C.,, and M. E. Grigg. 2002. Population biology of Toxoplasma gondii and its relevance to human infection: do different strains cause different disease? Curr. Opin. Microbiol. 5:438442.
20. Butcher, B. A.,, and E. Y. Denkers. 2002. Mechanism of entry determines ability of Toxoplasma gondii to inhibit macrophage proinflammatory cytokine production. Infect. Immun. 70:52165224.
21. Butcher, B. A.,, R. I. Greene,, S. C. Henry,, K. L. Annecharico,, J. B. Weinberg,, E. Y. Denkers,, A. Sher, and, G. A. Taylor. 2005a. p47 GTPases regulate Toxoplasma gondii survival in activated macrophages. Infect. Immun. 73:32783286.
22. Butcher, B. A.,, L. Kim,, P. F. Johnson, and, E. Y. Denkers. 2001. Toxoplasma gondii tachyzoites inhibit proinflammatory cytokine induction in infected macrophages by preventing nuclear translocation of the transcription factor NFκB. J. Immunol. 167:21932201.
23. Butcher, B. A.,, L. Kim,, A. Panopoulos,, S. S. Watowich,, P. J. Murray, and, E. Y. Denkers. 2005b. Cutting edge: IL-10-independent STAT3 activation by Toxoplasma gondii mediates suppression of IL-12 and TNF-α in host macrophages. J. Immunol. 174:31483152.
24. Camps, M.,, A. Nichols, and, S. Arkinstall. 2000. Dual specificity phosphatases: a gene family for control of MAP kinase function. FASEB J. 14:616.
25. Carruthers, V.,, and J. C. Boothroyd. 2007. Pulling together: an integrated model of Toxoplasma cell invasion. Curr. Opin. Microbiol. 10:8389.
26. Carruthers, V. B.,, O. K. Giddings, and, L. D. Sibley. 1999. Secretion of micronemal proteins is associated with toxoplasma invasion of host cells. Cell. Microbiol. 1:225235.
27. Carruthers, V. B.,, and L. D. Sibley. 1997. Sequential protein secretion from three distinct organelles of Toxoplasma gondii accompanies invasion of human fibroblasts. Eur. J. Cell Biol. 73:114123.
28. Cassatella, M. A. 1999. Neutrophil-derived proteins: selling cytokines by the pound. Adv. Immunol. 73:369509.
29. Chang, H. R.,, and J. C. Pechere. 1989. Macrophage oxidative metabolism and intracellular Toxoplasma gondii. Microb. Pathog. 7:3744.
30. Channon, J. Y.,, R. M. Seguin, and, L. H. Kasper. 2000. Differential infectivity and division of Toxoplasma gondii in human peripheral blood leukocytes. Infect. Immun. 68:48224826.
31. Charron, A. J.,, and L. D. Sibley. 2004. Molecular partitioning during host cell penetration by Toxoplasma gondii. Traffic 5:855867.
32. Chiao, P. J.,, S. Miyamato, and, I. M. Verma. 1994. Auto-regulation of IκBα activity. Proc. Natl. Acad. Sci. USA 91:2832.
33. Collazo, C. M.,, G. S. Yap,, G. D. Sempowski,, K. C. Lusby,, L. Tessarollo,, G. F. Vande Woude,, A. Sher, and, G. A. Taylor. 2001. Inactivation of LRG-47 and IRG-47 reveals a family of interferon-γ-inducible genes with essential, pathogen-specific roles in resistance to infection. J. Exp. Med. 194:181187.
34. Courret, N.,, S. Darche,, P. Sonigo,, G. Milon,, D. BuzoniGatel, and, I. Tardieux. 2006. CD11c and CD11b expressing mouse leukocytes transport single Toxoplasma gondii tachyzoites to the brain. Blood 107:309316.
35. Debierre-Grockiego, F.,, M. A. Campos,, N. Azzouz,, J. Schmidt,, U. Bieker,, M. G. Resende,, D. S. Mansur,, R. Weingart,, R. R. Schmidt,, D. T. Golenbock,, R. T. Gazzinelli, and, R. T. Schwarz. 2007. Activation of TLR2 and TLR4 by glycosylphosphatidylinositols derived from Toxoplasma gondii. J. Immunol. 179:11291137.
36. Deckert-Schluter, M.,, H. Bluethmann,, A. Rang,, H. Hof, and, D. Schluter. 1998. Crucial role for TNF receptor Type 1 (p55), but not TNF receptor Type 2 (p75), in murine toxoplasmosis. J. Immunol. 160:34273436.
37. Del Rio, L.,, S. Bennouna,, J. Salinas, and, E. Y. Denkers. 2001. CXCR2 deficiency confers impaired neutrophil recruitment and increased susceptibility during Toxoplasma gondii infection. J. Immunol. 167:65036509.
38. Del Rio, L.,, B. A. Butcher,, S. Bennouna,, S. Hieny,, A. Sher, and, E. Y. Denkers. 2004. Toxoplasma gondii triggers MyD88-dependent and CCL2(MCP-1) responses using distinct parasite molecules and host receptors. J. Immunol. 172:69546960.
39. Denkers, E. Y.,, B. A. Butcher,, L. Del Rio, and, S. Bennouna. 2004. Neutrophils, dendritic cells and Toxoplasma. Int. J. Parasitol. 34:411421.
40. Denkers, E. Y.,, B. A. Butcher,, L. Del Rio, and, L. Kim. 2004. Manipulation of mitogen-activated protein kinase/nuclear factor-κB-signaling cascades during intracellular Toxoplasma gondii infection. Immunol. Rev. 201:191205.
41. Denkers, E. Y.,, L. D. Del Rio, and, S. Bennouna. 2003. Neutrophil production of IL-12 and other cytokines during microbial infection. Chem. Immunol. Allergy 83:95114.
42. Denkers, E. Y.,, and R. T. Gazzinelli. 1998. Regulation and function of T cellmediated immunity during Toxoplasma gondii infection. Clin. Microbiol. Rev. 11:569588.
43. Denkers, E. Y.,, L. Kim, and, B. A. Butcher. 2003. In the belly of the beast: subversion of macrophage proinflammatory signaling cascades during Toxoplasma gondii infection. Cell. Microbiol. 5:7583.
44. Ding, M.,, L. Y. Kwok,, D. Schluter,, C. Clayton, and, D. Soldati. 2004. The antioxidant systems in Toxoplasma gondii and the role of cytosolic catalase in defence against oxidative injury. Mol. Microbiol. 51:4761.
45. Dobrowolski, J. M.,, and L. D. Sibley. 1996. Toxoplasma invasion of mammalian cells is powered by the actin cytoskeleton of the parasite. Cell 84:933939.
46. Dong, C.,, R. J. Davis, and, R. A. Flavell. 2002. MAP kinases in the immune response. Annu. Rev. Immunol. 20:5572.
47. Dubey, J. P. 1998. Advances in the life cycle of Toxoplasma gondii. Int. J. Parasitol. 28:10191024.
48. Dubey, J. P. 2007. The history and life-cycle of Toxoplasma gondii, p. 1–17. In L. M. Weiss and, K. Kim (ed.), Toxoplasma gondii. The Model Apicomplexan: Perspective and Methods. Academic Press, San Diego, CA.
49. Egan, C. E.,, W. Sukhumavasi,, A. L. Bierly, and, E. Y. Denkers. 2008. Understanding the multiple functions of Gr-1+ cell subpopulations during microbial infection. Immunol. Res. 40:3548.
50. El Hajj, H.,, M. Lebrun,, S. T. Arold,, H. Vial,, G. Labesse, and, J. F. Dubremetz. 2007. ROP18 is a rhoptry kinase controlling the intracellular proliferation of Toxoplasma gondii. PLoS Pathog. 3:e14.
51. Fox, B. A.,, and D. J. Bzik. 2002. De novo pyrimidine biosynthesis is required for virulence of Toxoplasma gondii. Nature 415:926929.
52. Fox, B. A.,, J. P. Gigley, and, D. J. Bzik. 2004. Toxoplasma gondii lacks the enzymes required for de novo arginine biosynthesis and arginine starvation triggers cyst formation. Int. J. Parasitol. 34:323331.
53. Gavrilescu, L. C.,, B. A. Butcher,, L. Del Rio,, G. A. Taylor, and, E. Y. Denkers. 2004. STAT1 is essential for antimicrobial function but dispensable for gamma interferon production during Toxoplasma gondii infection. Infect. Immun. 72:12571264.
54. Gavrilescu, L. C.,, and E. Y. Denkers. 2001. IFN-γ overproduction and high level apoptosis are associated with high but not low virulence Toxoplasma gondii infection. J. Immunol. 167:902909.
55. Gazzinelli, R.,, Y. Xu,, S. Hieny,, A. Cheever, and, A. Sher. 1992. Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii. J. Immunol. 149:175180.
56. Gazzinelli, R. T.,, and E. Y. Denkers. 2006. Protozoan encounters with Toll-like receptor signalling pathways: implications for host parasitism. Nat. Rev. Immunol. 6:895906.
57. Gazzinelli, R. T.,, F. T. Hakim,, S. Hieny,, G. M. Shearer, and, A. Sher. 1991. Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-γ production and protective immunity induced by an attenuated T. gondii vaccine. J. Immunol. 146:286292.
58. Gazzinelli, R. T.,, S. Hieny,, T. Wynn,, S. Wolf, and, A. Sher. 1993. IL-12 is required for the T-cell independent induction of IFN-γ by an intracellular parasite and induces resistance in T-cell-deficient hosts. Proc. Natl. Acad. Sci. USA 90:61156119.
59. Gazzinelli, R. T.,, I. P. Oswald,, S. Hieny,, S. James, and, A. Sher. 1992a. The microbicidal activity of interferon-γ-treated macrophages against Trypanosoma cruzi involves an L-arginine-dependent, nitrogen oxide-mediated mechanism inhibitable by interleukin-10 and transforming growth factor-β. Eur. J. Immunol. 22:25012506.
60. Gazzinelli, R. T.,, I. P. Oswald,, S. James, and, A. Sher. 1992b. IL-10 inhibits parasite killing and nitrogen oxide production by IFN-γ activated macrophages. J. Immunol. 148:17921796.
61. Gazzinelli, R. T.,, M. Wysocka,, S. Hayashi,, E. Y. Denkers,, S. Hieny,, P. Caspar,, G. Trinchieri, and, A. Sher. 1994. Parasite-induced IL-12 stimulates early IFN-γ synthesis and resistance during acute infection with Toxoplasma gondii. J. Immunol. 153:25332543.
62. Geissmann, F.,, S. Jung, and, D. R. Littman. 2003. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19:7182.
63. Gilbert, L. A.,, S. Ravindran,, J. M. Turetzky,, J. C. Boothroyd, and, P. J. Bradley. 2007. Toxoplasma gondii targets a protein phosphatase 2C to the nuclei of infected host cells. Eukaryot. Cell 6:7383.
64. Gubbels, M.-J.,, B. Striepen,, N. Shastri,, M. Turkoz, and, E. A. Robey. 2005. Class I major histocompatibility complex presentation of antigens that escape from the parasitophorous vacuole of Toxoplasma gondii. Infect. Immun. 73:703711.
65. Hakansson, S.,, A. J. Charron, and, L. D. Sibley. 2001. Toxoplasma evacuoles: a two-step process of secretion and fusion forms the parasitophorous vacuole. EMBO J. 20:31323144.
66. Heimesaat, M. M.,, S. Bereswill,, A. Fischer,, D. Fuchs,, D. Struck,, J. Niebergall,, H. K. Jahn,, I. R. Dunay,, A. Moter,, D. M. Gescher,, R. R. Schumann,, U. B. Gobel, and, O. Liesenfeld. 2006. Gram-negative bacteria aggravate murine small intestinal Th1-Type immunopathology following oral infection with Toxoplasma gondii. J. Immunol. 177:87858795.
67. Heimesaat, M. M.,, A. Fischer,, H. K. Jahn,, J. Niebergall,, M. Freudenberg,, M. Blaut,, O. Liesenfeld,, R. R. Schumann,, U. B. Gobel, and, S. Bereswill. 2007. Exacerbation of murine ileitis by toll-like receptor 4 meditated sensing of lipopolysaccharide from commensal Escherichia coli. Gut 56:941948.
68. Hitziger, N.,, I. Dellacasa,, B. Albiger, and, A. Barragan. 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. Microbiol. 6:837848.
69. Howe, D. K.,, and L. D. Sibley. 1995. Toxoplasma gondii comprises three clonal lineages: correlation of parasite genotype with human diseases. J. Infect. Dis. 172:15611566.
70. Hunter, C. A.,, E. Candolfi,, C. Subauste,, V. Van Cleave, and, J. S. Remington. 1995. Studies on the role of IL-12 in murine toxoplasmosis. Immunology 84:1621.
71. Johnson, L. L.,, and P. C. Sayles. 2002. Deficient humoral responses underlie susceptibility to Toxoplasma gondii in CD4-deficient mice. Infect. Immun. 70:185191.
72. Joiner, K. A. 1993. Cell entry by Toxoplasma gondii: all paths do not lead to success. Res. Immunol. 144:3438.
73. Joiner, K. A.,, S. A. Fuhrman,, H. M. Miettinen,, L. H. Kasper, and, I. Mellman. 1990. Toxoplasma gondii: fusion competence of parasitophorous vacuoles in Fc receptor-transfected fibroblasts. Science 249:641646.
74. Kang, H.,, J. S. Remington, and, Y. Suzuki. 2000. Decreased resistance of B cell-deficient mice to infection with Toxoplasma gondii despite unimpaired expression of IFN-γ, TNF-α, and inducible nitric oxide synthase. J. Immunol. 164:26292634.
75. Karin, M.,, and Y. Ben-Neriah. 2000. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18:621663.
76. Kasper, L.,, N. Courret,, S. Darche,, S. Luangsay,, F. Mennechet,, L. Minns,, N. Rachinel,, C. Ronet, and, D. BuzoniGatel. 2004. Toxoplasma gondii and mucosal immunity. Int. J. Parasitol. 34:401409.
77. Khan, A.,, C. Su,, M. German,, G. A. Storch,, D. B. Clifford, and, L. D. Sibley. 2005. Genotyping of Toxoplasma gondii strains from immunocompromised patients reveals high prevalence of type I strains. J. Clin. Microbiol. 43:58815887.
78. Khan, I. A.,, T. Matsuura, and, L. H. Kasper. 1994. Interleukin-12 enhances murine survival against acute toxoplasmosis. Infect. Immun. 62:16391645.
79. Kim, L.,, B. A. Butcher, and, E. Y. Denkers. 2004. Toxoplasma gondii interferes with lipopolysaccharide-induced mitogen-activated protein kinase activation by mechanisms distinct from endotoxin tolerance. J. Immunol. 172:30033010.
80. Kim, L.,, B. A. Butcher,, C. W. Lee,, S. Uematsu,, S. Akira, and, E. Y. Denkers. 2006. Toxoplasma gondii genotype determines MyD88-dependent signaling in infected macrophages. J. Immunol. 177:25842591.
81. Kim, L.,, L. Del Rio,, B. A. Butcher,, T. H. Mogensen,, S. Paludan,, R. A. Flavell, and, E. Y. Denkers. 2005. p38 MAPK autophosphorylation drives macrophage IL-12 production during intracellular infection. J. Immunol. 174:41784184.
82. Kim, L.,, and E. Y. Denkers. 2006. Toxoplasma gondii triggers Gi-dependent phosphatidylinositol 3-kinase signaling required for inhibition of host cell apoptosis. J. Cell Sci. 119:21192126.
83. Kim, S. K.,, A. E. Fouts, and, J. C. Boothroyd. 2007. Toxoplasma gondii dysregulates IFN-gamma-inducible gene expression in human fibroblasts: insights from a genome-wide transcriptional profiling. J. Immunol. 178:51545165.
84. Lambert, H.,, N. Hitziger,, I. Dellacasa,, M. Svensson, and, A. Barragan. 2006. Induction of dendritic cell migration upon Toxoplasma gondii infection potentiates parasite dissemination. Cell. Microbiol. 8:16111623.
85. Lang, C.,, M. Algner,, N. Beinert,, U. Gross, and, C. G. Luder. 2006. Diverse mechanisms employed by Toxoplasma gondii to inhibit IFN-gamma-induced major histocompatibility complex class II gene expression. Microbes Infect. 8:19942005.
86. Langermans, J. A. M.,, M. E. B. Van der Hulst,, P. H. Nibbereing,, P. S. Hiemstra,, L. Fransen, and, R. Van Furth. 1992. IFN-γ-induced L-arginine-dependent toxoplasmastatic activity in murine peritoneal macrophages is mediated by endogenous tumor necrosis factor-α. J. Immunol. 148:568578.
87. Lauw, F. N.,, D. R. Caffrey, and, D. T. Golenbock. 2005. Of mice and man: TLR11 (finally) finds profilin. Trends Immunol. 26:509511.
88. Lee, C. W.,, S. Bennouna, and, E. Y. Denkers. 2006. Screening for Toxoplasma gondii regulated transcriptional responses in LPS-activated macrophages. Infect. Immun. 74:19161923.
89. Lieberman, L. A.,, M. Banica,, S. L. Reiner, and, C. A. Hunter. 2004. STAT1 plays a critical role in the regulation of antimicrobial effector mechanisms, but not in the development of Th1-type responses during toxoplasmosis. J. Immunol. 172:457463.
90. Liesenfeld, O.,, S. Y. Wong, and, J. S. Remington. 1999. Toxoplasmosis in the setting of AIDS, p. 225–259. In J. G. Bartlett,, T. C. Merigan, and, D. Bolognesi (ed.), Textbook of AIDS Medicine. Williams and Wilkins, Baltimore, MD.
91. Ling, Y. M.,, M. H. Shaw,, C. Ayala,, I. Coppens,, G. A. Taylor,, D. J. Ferguson, and, G. S. Yap. 2006. Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages. J. Exp. Med. 203:20632071.
92. Liu, C. H.,, Y. T. Fan,, A. Dias,, L. Esper,, R. A. Corn,, A. Bafica,, F. S. Machado, and, J. Aliberti. 2006. Cutting edge: dendritic cells are essential for in vivo IL-12 production and development of resistance against Toxoplasma gondii infection in mice. J. Immunol. 177:3135.
93. Luder, C. G. K.,, M. Algner,, C. Lang,, N. Bleicher, and, U. Gross. 2003. Reduced expression of the inducible nitric oxide synthase after infection with Toxoplasma gondii facilitates parasite replication in activated murine macrophages. Int. J. Parasitol. 33:833844.
94. Luder, C. G. K.,, and U. Gross. 2005. Apoptosis and its modulation during infection with Toxoplasma gondii: molecular mechanisms and role in pathogenesis. Curr. Top. Microbiol. Immunol. 289:219238.
95. Luder, C. G. K.,, C. Lang,, M. Giraldo-Velasquez,, M. Algner,, J. Gerdes, and, U. Gross. 2003. Toxoplasma gondii inhibits MHC class II expression in neural antigen-presenting cells by down-regulating the class II transactivator CIITA. J. Neuroimmunol. 134:1224.
96. Luder, C. G. K.,, W. Walter,, B. Beuerle,, M. J. Maeurer, and, U. Gross. 2001. Toxoplasma gondii down-regulates MHC class II gene expression and antigen presentation by murine macrophages via interference with nuclear translocation of STAT1α. Eur. J. Immunol. 31:14751484.
97. Luft, B. J.,, R. G. Brooks,, F. K. Conley,, R. E. McCabe, and, J. S. Remington. 1984. Toxoplasmic encephalitis in patients with acquired immune response deficiency syndrome. JAMA 252:913917.
98. Luft, B. J.,, and J. S. Remington. 1992. Toxoplasmic encephalitis in AIDS. Clin. Infect. Dis. 15:211222.
99. Ma, W.,, K. Gee,, W. Lim,, K. Chambers,, J. B. Angel,, M. Kozlowski, and, A. Kumar. 2004. Dexamethasone inhibits IL-12p40 production in lipopolysaccharide-stimulated human monocytic cells by down-regulating the activity of c-Jun N-terminal kinase, the activation protein-1, and NF-kappa B transcription factors. J. Immunol. 172:318330.
100. MacMicking, J.,, Q. Xie, and, C. Nathan. 1997. Nitric oxide and macrophage function. Annu. Rev. Immunol. 15:323350.
101. Martens, S.,, I. Parvanova,, J. Zerrahn,, G. Griffiths,, G. Schell,, G. Reichmann, and, J. C. Howard. 2005. Disruption of Toxoplasma gondii parasitophorous vacuoles by the mouse p47-resistance GTPases. PLoS Pathog. 1:e24.
102. Masek, K. S.,, J. Fiore,, M. Leitges,, S. F. Yan,, B. D. Freedman, and, C. A. Hunter. 2006. Host cell Ca2+ and protein kinase C regulate innate recognition of Toxoplasma gondii. J. Cell Sci. 119:45654573.
103. Mason, N.,, J. Aliberti,, J. C. Caamano,, H. C. Liou, and, C. A. Hunter. 2002. Identification of c-Rel-dependent and -independent pathways of Il-12 production during infectious and inflammatory stimuli. J. Immunol. 168:25902594.
104. McKee, A. S.,, F. Dzierszinski,, M. Boes,, D. S. Roos, and, E. J. Pearce. 2004. Functional inactivation of immature dendritic cells by the intracellular parasite Toxoplasma gondii. J. Immunol. 173:26322640.
105. Megiovanni, A. M.,, F. Sanchez,, M. Robledo-Sarmiento,, C. Morel,, J. C. Gluckman, and, S. Boudaly. 2006. Polymorphonuclear neutrophils deliver activation signals and antigenic molecules to dendritic cells: a new link between leukocytes upstream of T lymphocytes. J. Leukoc. Biol. 79:977988.
106. Mercier, C.,, K. D. Adjogble,, W. Daubener, and, M. F. Delauw. 2005. Dense granules: are they key organelles to help understand the parasitophorous vacuole of all apicomplexa parasites? Int. J. Parasitol. 35:829849.
107. Minns, L. A.,, L. C. Menard,, D. M. Foureau,, S. Darche,, C. Ronet,, D. W. Mielcarz,, D. Buzoni-Gatel, and, L. H. M. Kasper. 2006. TLR9 is required for the gut-associated lymphoid tissue response following oral infection of Toxoplasma gondii. J. Immunol. 176:75897597.
108. Mital, J.,, M. Meissner,, D. Soldati, and, G. E. Ward. 2005. Conditional expression of Toxoplasma gondii apical membrane antigen-1 (TgAMA1) demonstrates that TgAMA1 plays a critical role in host cell invasion. Mol. Biol. Cell 16:43414349.
109. Molestina, R. E.,, T. M. Payne,, I. Coppens, and, A. P. Sinai. 2003. Activation of NF-κB by Toxoplasma gondii correlates with increased expression of antiapoptotic genes and localization of phosphorylated IκB to the parasitophorous vacuole membrane. J. Cell Sci. 116:43594371.
110. Moore, K. A.,, R. de Waal Malefyt,, R. L. Coffman, and, A. O’Garra. 2001. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19:683765.
111. Mordue, D. G.,, N. Dessai,, M. Dustin, and, L. D. Sibley. 1999. Invasion by Toxoplasma gondii establishes a moving junction that selectively excludes host cell plasma membrane proteins on the basis of their membrane anchoring. J. Exp. Med. 190:17831792.
112. Mordue, D. G.,, F. Monroy,, M. La Regina,, C. A. Dinarello, and, L. D. Sibley. 2001. Acute toxoplasmosis leads to lethal overproduction of Th1 cytokines. J. Immunol. 167:45744584.
113. Mordue, D. G.,, and L. D. Sibley. 1997. Intracellular fate of vacuoles containing Toxoplasma gondii is determined at the time of formation and depends upon the mechanism of entry. J. Immunol. 159:44524459.
114. Mordue, D. G.,, and L. D. Sibley. 2003. A novel population of Gr-1+-activated macrophages induced during acute toxoplasmosis. J. Leukoc. Biol. 74:111.
115. Morisaki, J. H.,, J. E. Heuser, and, L. D. Sibley. 1995. Invasion of Toxoplasma gondii occurs by active penetration of the host cell. J. Cell Sci. 108:24572464.
116. Moudy, R.,, T. J. Manning, and, C. J. Beckers. 2001. The loss of cytoplasmic potassium upon host cell breakdown triggers egress of Toxoplasma gondii. J. Biol. Chem. 276:4149241501.
117. Mun, H.-S.,, F. Aosai,, K. Norose,, M. Chen,, L.-X. Piao,, O. Takeuchi,, S. Akira,, H. Ishikura, and, A. Yano. 2003. TLR2 as an essential molecule for protective immunity against Toxoplasma gondii infection. Int. Parasitol. 15:10811087.
118. Murray, H. W.,, C. W. Juangbhanich,, C. F. Nathan, and, Z. A. Cohn. 1979. Macrophage oxygen-dependent antimicrobial activity. II. The role of oxygen intermediates. J. Exp. Med. 150:950964.
119. Murray, H. W.,, B. Y. Rubin,, S. M. Carriero,, A. M. Harris, and, E. A. Jaffee. 1985. Human mononuclear phagocyte antiprotozoal mechanisms: oxygen-dependent vs oxygen-independent activity against intracellular Toxoplasma gondii. J. Immunol. 134:19821988.
120. O’Neill L, A.,, and A. G. Bowie. 2007. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat. Rev. Immunol. 7:353364.
121. Pierce, K. L.,, R. T. Premont, and, R. J. Lefkowitz. 2002. Seven-transmembrane receptors. Nat. Rev. Mol. Cell Biol. 3:639650.
122. Platanias, L. C. 2005. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol. 5:375386.
123. Reis e Sousa, C.,, S. Hieny,, T. Scharton-Kersten,, D. Jankovic,, H. Charest,, R. N. Germain, and, A. Sher. 1997. In vivo microbial stimulation induces rapid CD40-L-independent production of IL-12 by dendritic cells and their re-distribution to T cell areas. J. Exp. Med. 186:18191829.
124. Remington, J. S.,, R. McLeod,, P. Thuliez, and, G. Desmonts. 2001. Toxoplasmosis, p. 205–346. In J. S. Remington and, J. O. Klein (ed.), Infectious Diseases of the Fetus and Newborn Infant, 3rd ed. W. B. Saunders Co., Philadelphia, PA.
125. Roach, J. C.,, G. Glusman,, L. Rowen,, A. Kaur,, M. K. Purcell,, K. D. Smith,, L. E. Hood, and, A. Aderem. 2005. The evolution of vertebrate Toll-like receptors. Proc. Natl. Acad. Sci. USA 102:95779582.
126. Robben, P. M.,, M. LaRegina,, W. A. Kuziel, and, L. D. Sibley. 2005. Recruitment of Gr-1+ monocytes is essential for control of acute toxoplasmosis. J. Exp. Med. 201:17611769.
127. Robben, P. M.,, D. G. Mordue,, S. M. Truscott,, K. Takeda,, S. Akira, and, L. D. Sibley. 2004. Production of IL-12 by macrophages infected with Toxoplasma gondii depends on the parasite genotype. J. Immunol. 172:36863694.
128. Saavedra, R.,, M. A. Becerril,, C. Dubeaux,, R. Lippens,, M. J. De Vos,, P. Herion, and, A. Bollen. 1996. Epitopes recognized by human T lymphocytes in the ROP2 protein antigen of Toxoplasma gondii. Infect. Immun. 64:38583862.
129. Saeij, J. P.,, J. P. Boyle,, S. Coller,, S. Taylor,, L. D. Sibley,, E. T. Brooke-Powell,, J. W. Ajioka, and, J. C. Boothroyd. 2006. Polymorphic secreted kinases are key virulence factors in toxoplasmosis. Science 314:17801783.
130. Saeij, J. P.,, S. Coller,, J. P. Boyle,, M. E. Jerome,, M. W. White, and, J. C. Boothroyd. 2007. Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue. Nature 445:324327.
131. Sayles, P. C.,, G. W. Gibson, and, L. L. Johnson. 2000. B cells are essential for vaccination-induced resistance to virulent Toxoplasma gondii. Infect. Immun. 68:10261033.
132. Scanga, C. A.,, J. Aliberti,, D. Jankovic,, F. Tilloy,, S. Bennouna,, E. Y. Denkers,, R. Medzhitov, and, A. Sher. 2002. Cutting edge: MyD88 is required for resistance to Toxoplasma gondii infection and regulates parasite-induced IL-12 production by dendritic cells. J. Immunol. 168:59976001.
133. Scharton-Kersten, T.,, G. Yap,, J. Magram, and, A. Sher. 1997. Inducible nitric oxide is essential for host control of persistent but not acute infection with the intracellular pathogen Toxoplasma gondii. J. Exp. Med. 185:113.
134. Scharton-Kersten, T. M.,, T. A. Wynn,, E. Y. Denkers,, S. Bala,, L. Showe,, E. Grunvald,, S. Hieny,, R. T. Gazzinelli, and, A. Sher. 1996. In the absence of endogenous IFN-γ mice develop unimpaired IL-12 responses to Toxoplasma gondii while failing to control acute infection. J. Immunol. 157:40454054.
135. Schwab, J. C.,, C. J. M. Beckers, and, K. A. Joiner. 1994. The parasitophorous vacuole membrane surrounding intracellular Toxoplasma gondii functions as a molecular sieve. Proc. Natl. Acad. Sci. USA 91:509513.
136. Serbina, N. V.,, T. P. Salazar-Mathar,, C. A. Biron,, W. A. Kuziel, and, E. A. Pamer. 2003. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19:5970.
137. Shapira, S.,, O. Harb,, J. Margarit,, M. Matrajt,, J. Han,, A. Hoffmann,, B. Freedman,, M. J. May,, D. S. Roos, and, C. A. Hunter. 2005. Initiation and termination of NFκB signaling by the intracellular protozoan parasite Toxoplasma gondii. J. Cell Sci. 118:35013508.
138. Shapira, S. S.,, K. Speirs,, A. Gerstein,, J. Caamano, and, C. A. Hunter. 2002. Suppression of NF-κB activation by infection with Toxoplasma gondii. J. Infect. Dis. 185:S66S72.
139. Sibley, L. D.,, and J. C. Boothroyd. 1992. Virulent strains of Toxoplasma gondii comprise a single clonal lineage. Nature 359:8285.
140. Sibley, L. D.,, A. Charron,, S. Hakansson, and, D. Mordue. 2007. Invasion and intracellular survival by Toxoplasma, p. 16–24. In E. Y. Denkers and, R. T. Gazzinelli (ed.), Protozoans in Macrophages. Landes Bioscience, Austen, TX.
141. Sibley, L. D.,, R. Lawson, and, J. L. Krahenbuhl. 1985. Phagosome acidification blocked by intracellular Toxoplasma gondii. Nature 315:416419.
142. Sibley, L. D.,, D. G. Mordue,, C. Su,, P. M. Robben, and, D. K. Howe. 2002. Genetic approaches to studying virulence and pathogenesis in Toxoplasma gondii. Philos. Trans. R. Soc. Lond. 357:8188.
143. Sinai, A. P.,, and K. A. Joiner. 2001. The Toxoplasma gondii protein ROP2 mediates host organelle association with the parasitophorous vacuole membrane. J. Cell Biol. 154:95108.
144. Singh, S. B.,, A. S. Davis,, G. A. Taylor, and, V. Deretic. 2006. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313:14381441.
145. Subauste, C. S.,, and M. Wessendarp. 2000. Human dendritic cells discriminate between viable and killed Toxoplasma gondii tachyzoites: dendritic cell activation after infection with viable parasites results in CD28 and CD40 ligand signaling that controls IL-12-dependent and -independent T cell production of IFN-γ. J. Immunol. 165:14981505.
146. Subauste, C. S.,, and M. Wessendarp. 2006. CD40 restrains in vivo growth of Toxoplasma gondii independently of gamma interferon. Infect. Immun. 74:15731579.
147. Subauste, C. S.,, M. Wessendarp,, R. U. Sorensen, and, L. E. Leiva. 1999. CD40-CD40 ligand interaction is central to cellmediated immunity against Toxoplasma gondii: patients with hyper IgM syndrome have a defective Type I immune response that can be restored by soluble CD40 ligand trimer. J. Immunol. 162:66906700.
148. Sumyuen, M. H.,, Y. J. Garin, and, F. Derouin. 1995. Early kinetics of Toxoplasma gondii infection in mice infected orally with cysts of an avirulent strain. J. Parasitol. 81:327329.
149. Suss-Toby, E.,, E. J. Zimmerberg, and, G. E. Ward. 1996. Toxoplasma invasion: the parasitophorous vacuole is formed from host cell plasma membrane and pinches off via a fusion pore. Proc. Natl. Acad. Sci. USA 93:84138418.
150. Suzuki, Y.,, F. K. Conley, and, J. S. Remington. 1989. Importance of endogenous IFN-γ for the prevention of toxoplasmic encephalitis in mice. J. Immunol. 143:20452050.
151. Suzuki, Y.,, M. A. Orellana,, R. D. Schreiber, and, J. S. Remington. 1988. Interferon-γ: the major mediator of resistance against Toxoplasma gondii. Science 240:516518.
152. Suzuki, Y.,, and J. S. Remington. 1988. Dual regulation of resistance against Toxoplasma gondii infection by Lyt-2+ and Lyt1+,L3T4+ T cells in mice. J. Immunol. 140:39433946.
153. Taylor, G. A. 2007. IRG proteins: key mediators of interferon-regulated host resistance to intracellular pathogens. Cell. Microbiol. 9:10991107.
154. Taylor, G. A.,, C. M. Collazo,, G. S. Yap,, K. Nguyen,, T. A. Gregorio,, L. S. Taylor,, B. Eagleson,, L. Secret,, E. A. Southon,, S. W. Reid,, L. Tessarollo,, M. Bray,, D. W. McVicar,, K. L. Komschlies,, H. A. Young,, C. A. Biron,, A. Sher, and, G. F. Vande Woude. 2000. Pathogen-specific loss of host resistance in mice lacking the IFN-γ-inducible gene IGTP. Proc. Natl. Acad. Sci. USA 97:751755.
155. Taylor, G. A.,, C. G. Feng, and, A. Sher. 2004. p47 GTPases: regulators of immunity to intracellular pathogens. Nat. Rev. Immunol. 4:100109.
156. Taylor, S.,, A. Barragan,, C. Su,, B. Fux,, S. J. Fentress,, K. Tang,, W. L. Beatty,, H. E. Hajj,, M. Jerome,, M. S. Behnke,, M. White,, J. C. Wootton, and, L. D. Sibley. 2006. A secreted serine-threonine kinase determines virulence in the eukaryotic pathogen Toxoplasma gondii. Science 314:17761780.
157. Valere, A.,, R. Garnotel,, I. Villena,, M. Guenounou,, J. M. Pinon, and, D. Aubert. 2003. Activation of the cellular mitogen-activated protein kinase pathways ERK. p38 and JNK during Toxoplasma gondii invasion. Parasite 10:5964.
158. van Gisbergen, K. P.,, T. B. Geijtenbeek, and, Y. van Kooyk. 2005a. Close encounters of neutrophils and DCs. Trends Immunol. 26:626631.
159. van Gisbergen, K. P.,, M. Sanchez-Hernandez,, T. B. Geijteenbeek, and, Y. van Kooyk. 2005b. Neutrophils mediate immune modulation of dendritic cells through glycosylation-dependent interactions between Mac-1 and DC-SIGN. J. Exp. Med. 201:12811292.
160. Williams, L.,, L. Bradley,, A. Smith, and, B. Foxwell. 2004. Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages. J. Immunol. 172:567576.
161. Wilson, C. B.,, and J. S. Remington. 1979. Activity of human blood leukocytes against Toxoplasma gondii. J. Infect. Dis. 140:890895.
162. Wilson, C. B.,, V. Tsai, and, J. S. Remington. 1980. Failure to trigger the oxidative metabolic burst by normal macrophages: possible mechanism for survival of intracellular pathogens. J. Exp. Med. 151:328346.
163. Yarovinsky, F.,, and A. Sher. 2006. Toll-like receptor recognition of Toxoplasma gondii. Int. J. Parasitol. 36:255259.
164. Yarovinsky, F.,, D. Zhang,, J. F. Anderson,, G. L. Bannenberg,, C. N. Serhan,, M. S. Hayden,, S. Hieny,, F. S. Sutterwala,, R. A. Flavell,, S. Ghosh, and, A. Sher. 2005. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308:16261629.
165. Zimmermann, S.,, P. J. Murray,, K. Heeg, and, A. H. Dalpke. 2006. Induction of suppressor of cytokine signaling-1 by Toxoplasma gondii contributes to immune evasion in macrophages by blocking IFN-[gamma] signaling. J. Immunol. 176:18401847.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error