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

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 pathw...

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Autores principales: Mercer, Heather L., Snyder, Lindsay M., Doherty, Claire M., Fox, Barbara A., Bzik, David J., Denkers, Eric Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255617/
https://www.ncbi.nlm.nih.gov/pubmed/32413093
http://dx.doi.org/10.1371/journal.ppat.1008572
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author Mercer, Heather L.
Snyder, Lindsay M.
Doherty, Claire M.
Fox, Barbara A.
Bzik, David J.
Denkers, Eric Y.
author_facet Mercer, Heather L.
Snyder, Lindsay M.
Doherty, Claire M.
Fox, Barbara A.
Bzik, David J.
Denkers, Eric Y.
author_sort Mercer, Heather L.
collection PubMed
description 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.
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spelling pubmed-72556172020-06-08 Toxoplasma gondii dense granule protein GRA24 drives MyD88-independent p38 MAPK activation, IL-12 production and induction of protective immunity Mercer, Heather L. Snyder, Lindsay M. Doherty, Claire M. Fox, Barbara A. Bzik, David J. Denkers, Eric Y. PLoS Pathog Research Article 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. Public Library of Science 2020-05-15 /pmc/articles/PMC7255617/ /pubmed/32413093 http://dx.doi.org/10.1371/journal.ppat.1008572 Text en © 2020 Mercer et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Mercer, Heather L.
Snyder, Lindsay M.
Doherty, Claire M.
Fox, Barbara A.
Bzik, David J.
Denkers, Eric Y.
Toxoplasma gondii dense granule protein GRA24 drives MyD88-independent p38 MAPK activation, IL-12 production and induction of protective immunity
title Toxoplasma gondii dense granule protein GRA24 drives MyD88-independent p38 MAPK activation, IL-12 production and induction of protective immunity
title_full Toxoplasma gondii dense granule protein GRA24 drives MyD88-independent p38 MAPK activation, IL-12 production and induction of protective immunity
title_fullStr Toxoplasma gondii dense granule protein GRA24 drives MyD88-independent p38 MAPK activation, IL-12 production and induction of protective immunity
title_full_unstemmed Toxoplasma gondii dense granule protein GRA24 drives MyD88-independent p38 MAPK activation, IL-12 production and induction of protective immunity
title_short Toxoplasma gondii dense granule protein GRA24 drives MyD88-independent p38 MAPK activation, IL-12 production and induction of protective immunity
title_sort toxoplasma gondii dense granule protein gra24 drives myd88-independent p38 mapk activation, il-12 production and induction of protective immunity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255617/
https://www.ncbi.nlm.nih.gov/pubmed/32413093
http://dx.doi.org/10.1371/journal.ppat.1008572
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