title: Toxoplasma gondii genotype determines MyD88-dependent signaling in infected macrophages.
abstract: Infection of mouse macrophages with Toxoplasma gondii elicits MAPK activation and IL-12 production, but host cell signaling pathways have not been clearly delineated. Here, we compared macrophage signaling in response to high virulence type I (RH) vs low virulence type II (ME49) strain infection. Tachyzoites of both strains induced p38 MAPK-dependent macrophage IL-12 release, although ME49 elicited 2- to 3-fold more cytokine than RH. IL-12 production was largely restricted to infected cells in each case. RH-induced IL-12 release did not require MyD88, whereas ME49-triggered IL-12 production was substantially dependent on this TLR/IL-1R adaptor molecule. MyD88 was also not required for RH-stimulated p38 MAPK activation, which occurred in the absence of detectable upstream p38 MAPK kinase activity. In contrast, ME49-driven p38 MAPK activation displayed an MyD88-dependent component. This parasite strain also induced MyD88-dependent activation of MKK4, an upstream activator of p38 MAPK. The results suggest that RH triggers MAPK activation and IL-12 production using MyD88-independent signaling, whereas ME49 uses these pathways as well as MyD88-dependent signaling cascades. Differences in host signaling pathways triggered by RH vs ME49 may contribute to the high and low virulence characteristics displayed by these parasite strains.
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Leesun
authors.initials: L
authors.lastname: Kim
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Butcher
authors.forename: Chiang W
authors.initials: CW
authors.lastname: Lee
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Denkers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D005260:Female; D005838:Genotype; D007113:Immunity, Innate; D018664:Interleukin-12 / Q000096:biosynthesis; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000469:parasitology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D015398:Signal Transduction / Q000276:immunology*; D013045:Species Specificity; D014122:Toxoplasma / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity; D014774:Virulence; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D018664:Interleukin-12; D048051:p38 Mitogen-Activated Protein Kinases