Toxoplasma gondii dense granule protein GRA24 drives MyD88-independent p38 MAPK activation, IL-12 production and induction of protective immunity
| Autor: | Barbara A. Fox, Heather L. Mercer, Claire M. Doherty, Eric Y. Denkers, David J. Bzik, Lindsay M. Snyder |
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| Rok vydání: | 2020 |
| Předmět: |
Chemokine
Physiology Protozoan Proteins Biochemistry Immune Receptors p38 Mitogen-Activated Protein Kinases Toxoplasma Gondii Mice Immune Physiology Medicine and Health Sciences Enzyme-Linked Immunoassays Biology (General) Receptor Toll-like Receptors Protozoans Mice Knockout Innate Immune System 0303 health sciences Immune System Proteins biology Nucleotides Chemistry 030302 biochemistry & molecular biology Eukaryota Interleukin-12 Cell biology Interleukin 12 Cytokines Toxoplasma Toxoplasmosis Research Article Signal Transduction MAP Kinase Signaling System QH301-705.5 p38 mitogen-activated protein kinases Immunology CD11c Research and Analysis Methods Microbiology 03 medical and health sciences Virology Parasite Groups Parasitic Diseases Genetics Animals Uracils Immunoassays Molecular Biology 030304 developmental biology Nucleobases Macrophages Organisms Wild type Biology and Life Sciences Proteins Toxoplasma gondii Cell Biology Molecular Development RC581-607 biology.organism_classification Parasitic Protozoans Enzyme Activation Immune System Myeloid Differentiation Factor 88 Immunologic Techniques biology.protein Tachyzoites Parasitology Immunologic diseases. Allergy Dense granule Apicomplexa Developmental Biology |
| Zdroj: | PLoS Pathogens, Vol 16, Iss 5, p e1008572 (2020) PLoS Pathogens |
| ISSN: | 1553-7374 |
| DOI: | 10.1371/journal.ppat.1008572 |
| Popis: | 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. Author summary Toxoplasma gondii is a protozoan parasite that infects over 1 billion people worldwide. Infection with the parasite is normally asymptomatic and Toxoplasma co-exists with its host in the form of latent cysts in brain and muscle tissue. The balance between immune recognition and immune evasion is likely a key factor in the outcome of this host-parasite interaction. It is therefore important to understand how Toxoplasma triggers immunity, and in particular how the protective cytokine IL-12 is induced during infection. While Toll-like receptor (TLR)/MyD88 signaling is important in mouse resistance to Toxoplasma, this pathway is likely less important in human infection. Here, we report that the parasite dense granule protein GRA24 triggers p38 MAPK activation and IL-12 production independently of TLR/MyD88 signaling. We identify additional cytokines and chemokines that are regulated by GRA24 during in vivo infection. Our data demonstrate that GRA24 initiates a protective MyD88-independent immune response during in vivo infection. The GRA24 molecule provides an example of a parasite molecule whose function is induction of a host protective immune response. From the standpoint of Toxoplasma, this likely reflects an evolutionary adaptation to ensure host survival and simultaneously enable latency to maximize the chance of transmission. |
| Databáze: | OpenAIRE |
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