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Parasitized Natural Killer cells do not facilitate the spread of Toxoplasma gondii to the brain.

ABSTRACT: Toxoplasma gondii is a protozoan parasite capable of invading immune cells and co-opting their migratory pathways to disseminate through the host. Natural Killer (NK) cells can be directly invaded by the parasite and this invasion alters NK cell migration, producing a hypermotile phenotype. However, the consequences of this hypermotile phenotype for the dissemination of T. gondii to the brain remain unknown. To address this, C57BL6/J mice were infected with freshly egressed tachyzoites (type IIPrugniaud strain) or with parasitized NK cells. Under both conditions, parasite loads in the brain were comparable, indicating that parasitized NK cells were not able to facilitate spread of T. gondii to the brain. Consistent with this, we found no evidence for the recruitment of endogenous NK cells to the brain at early time points post-infection, nor any changes in the expression of ?4?1 integrin, involved in recruitment of NK cells to the brain. We therefore found no evidence for a role for hypermotile NK cells in delivery of parasites to the brain during acute infection with T. gondii.

SUBMITTER: Petit-Jentreau L

PROVIDER: S-EPMC5901034 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Parasitized Natural Killer cells do not facilitate the spread of Toxoplasma gondii to the brain.

Petit-Jentreau L L Glover C C Coombes J L JL

Parasite immunology 20180325 4

Toxoplasma gondii is a protozoan parasite capable of invading immune cells and co-opting their migratory pathways to disseminate through the host. Natural Killer (NK) cells can be directly invaded by the parasite and this invasion alters NK cell migration, producing a hypermotile phenotype. However, the consequences of this hypermotile phenotype for the dissemination of T. gondii to the brain remain unknown. To address this, C57BL6/J mice were infected with freshly egressed tachyzoites (type IIP ...[more]

PMID: 29478283

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Project description:As a response to a diverse array of external stimuli, early growth response protein 1 (Egr-1) plays important roles in the transcriptional regulation of inflammation and the cellular immune response. However, a number of intracellular pathogens colonize immune cells and the implication of Egr-1 in the host-pathogen interplay has remained elusive. Here, we have characterized the Egr-1 responses of primary murine and human dendritic cells (DCs) upon challenge with the obligate intracellular parasite Toxoplasma gondii. We report that live intracellular parasites induce a sustained high expression of Egr-1 in DCs, different from the immediate-early Egr-1 response to parasite lysates, inactivated parasites or LPS. Moreover, a distinct nuclear localization of elevated amounts of Egr-1 protein was detected in infected DCs, but not in by-stander DCs. The ERK1/2 MAPK signaling pathway mediated the canonical immediate-early Egr-1 response to soluble antigens in a MyD88/TLR-dependent fashion. In contrast, a non-canonical extended Egr-1 response that relied primarily on p38 MAPK signaling was induced by intracellular parasites and was exhibited similarly by MyD88-deficient and wildtype DCs. The extended phase Egr-1 response was dramatically reduced upon challenge of DCs with T. gondii parasites deficient in GRA24, a secreted p38-interacting protein. Further, Egr-1-silenced primary DCs maintained their migratory responses upon T. gondii challenge. Importantly, Egr-1 silencing led to elevated expression of co-stimulatory molecules (CD40, CD80) in Toxoplasma-infected DCs and in LPS-challenged immature DCs, indicating that Egr-1 responses suppressed maturation of DCs. Moreover, the IL-12 and IL-2 responses of Toxoplasma-challenged DCs were modulated in a GRA24-dependent fashion. Jointly, the data show that the Egr-1 responses of DCs to microbial external stimuli and intracellular stimuli can be selectively mediated by ERK1/2 or p38 MAPK signaling, and that Egr-1 can act as an intrinsic negative modulator of maturation in primary DCs.

Dataset Information

Parasitized Natural Killer cells do not facilitate the spread of Toxoplasma gondii to the brain.

Publications

Parasitized Natural Killer cells do not facilitate the spread of Toxoplasma gondii to the brain.

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