Toxoplasma gondii dense granule protein GRA24 drives MyD88-independent p38 MAPK activation, IL-12 production and induction of protective immunity

English version

Autoři: Heather L. Mercer ^aff001; Lindsay M. Snyder ^aff001; Claire M. Doherty ^aff001; Barbara A. Fox ^aff002; David J. Bzik ^aff002; Eric Y. Denkers ^aff001
Působiště autorů: Center for Evolutionary and Theoretical Immunology and Department of Biology, University of New Mexico, Albuquerque, New Mexico, United States of America ^aff001; Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America ^aff002
Vyšlo v časopise: Toxoplasma gondii dense granule protein GRA24 drives MyD88-independent p38 MAPK activation, IL-12 production and induction of protective immunity. PLoS Pathog 16(5): e32767. doi:10.1371/journal.ppat.1008572
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008572

Souhrn

The apicomplexan Toxoplasma gondii induces strong protective immunity dependent upon recognition by Toll-like receptors (TLR)11 and 12 operating in conjunction with MyD88 in the murine host. However, TLR11 and 12 proteins are not present in humans, inspiring us to investigate MyD88-independent pathways of resistance. Using bicistronic IL-12-YFP reporter mice on MyD88^+/+ and MyD88^-/- genetic backgrounds, we show that CD11c⁺MHCII⁺F4/80^- dendritic cells, F4/80⁺ macrophages, and Ly6G⁺ neutrophils were the dominant cellular sources of IL-12 in both wild type and MyD88 deficient mice after parasite challenge. Parasite dense granule protein GRA24 induces p38 MAPK activation and subsequent IL-12 production in host macrophages. We show that Toxoplasma triggers an early and late p38 MAPK phosphorylation response in MyD88^+/+ and MyD88^-/- bone marrow-derived macrophages. Using the uracil auxotrophic Type I T. gondii strain cps1-1, we demonstrate that the late response does not require active parasite proliferation, but strictly depends upon GRA24. By i. p. inoculation with cps1-1 and cps1-1:Δgra24, we identified unique subsets of chemokines and cytokines that were up and downregulated by GRA24. Finally, we demonstrate that cps1-1 triggers a strong host-protective GRA24-dependent Th1 response in the absence of MyD88. Our data identify GRA24 as a major mediator of p38 MAPK activation, IL-12 induction and protective immunity that operates independently of the TLR/MyD88 cascade.

Klíčová slova:

Cytokines – Enzyme-linked immunoassays – Parasitic diseases – Toll-like receptors – Toxoplasma – Toxoplasma gondii – Tachyzoites – Uracils

Zdroje

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