In the belly of the beast: subversion of macrophage proinflammatory signalling cascades during Toxoplasma gondii infection.
Macrophages (MØ) are used as the intracellular niche by several bacterial and protozoan microorganisms. Such microbial pathogens adopt diverse strategies to avoid MØ microbicidal effects. Recent insights into the Toxoplasma gondii-MØ interaction reveal novel ways that intracellular parasites subvert MØ function. In contrast to some microbial pathogens, Toxoplasma infection is not silent but induces rapid activation of transcription factors such as STAT-1 and NFkappaB. However, the parasite blocks nuclear translocation of both factors, and MØ cannot produce IL-12 or TNF-alpha when subsequently triggered with lipopolysaccharide. The nuclear import blockade is lifted 24 h after infection, but cells remain actively suppressed in TNF-alpha production. Nevertheless, IL-12 synthesis is initiated at this later time point. Toxoplasma gondii-induced production of this cytokine occurs through both MyD88- and CCR5-dependent pathways. The balance of cytokine subversion and stimulation during infection probably results from the parasite's need to simultaneously avoid immune elimination and trigger immunity to prevent host death.
Denkers
Eric Y
EY
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401, USA. eyd1@cornell.edu
Kim
Leesun
L
Butcher
Barbara A
BA
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology; D002467:Cell Nucleus / Q000469:parasitology; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000469:parasitology / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000096:biosynthesis; D019713:Receptors, CCR5 / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D014122:Toxoplasma / Q000276:immunology; D014123:Toxoplasmosis / Q000276:immunology*; D015534:Trans-Activators / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D019713:Receptors, CCR5; D011971:Receptors, Immunologic; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12