Convergent Met and voltage-gated Ca2+ channel signaling drives hypermigration of <i>Toxoplasma</i>-infected dendritic cells

Ólafsson, Einar B.; Hoeve, Arne L. ten; Li-Wang, Xiaoze; Westermark, Linda; Varas-Godoy, Manuel; Barragán, Antonio

doi:10.1242/jcs.241752

Cited by 13 publications

(20 citation statements)

References 60 publications

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“…ERK1/2 phosphorylation increased transiently 1 h after infection by both strains and decreased afterwards. At later time points, however, infection by ME49 led to a gradually increased and sustained phosphorylation of ERK1/2, an observation in line with a recent study that reported a similar trend in bone marrow-derived dendritic cells infected with Prugniaud, another type II strain (Olafsson et al, 2020). Meanwhile, phospho-ERK1/2 levels in RH-infected cells remained low and comparable to basal levels seen in uninfected cultures.…”

Section: Discussionsupporting

confidence: 88%

Infection by the Protozoan Parasite Toxoplasma gondii Inhibits Host MNK1/2-eIF4E Axis to Promote Its Survival

Leroux

Chaparro

Jaramillo

2020

Front. Cell. Infect. Microbiol.

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The obligate intracellular parasite Toxoplasma gondii reprograms host gene expression through multiple mechanisms that promote infection, including the up-regulation of mTOR-dependent host mRNA translation. In addition to the mTOR-4E-BP1/2 axis, MAPK-interacting kinases 1 and 2 (MNK1/2) control the activity of the mRNA cap-binding protein eIF4E. Herein, we show that T. gondii inhibits the phosphorylation of MNK1/2 and their downstream target eIF4E in murine and human macrophages. Exposure to soluble T. gondii antigens (STAg) failed to fully recapitulate this phenotype indicating the requirement of live infection. Treatment with okadaic acid, a potent phosphatase inhibitor, restored phosphorylation of MNK1/2 and eIF4E regardless of infection. T. gondii replication was higher in macrophages isolated from mice mutated at the residue where eIF4E is phosphorylated (eIF4E S209A knock-in) than in wild-type (WT) control cells despite no differences in infection rates. Similarly, parasitemia in the mesenteric lymph nodes and spleen, as well as brain cyst burden were significantly augmented in infected eIF4E S209A knock-in mice compared to their WT counterparts. Of note, mutant mice were more susceptible to acute toxoplasmosis and displayed exacerbated levels of IFNγ. In all, these data suggest that the MNK1/2-eIF4E axis is required to control T. gondii infection and that its inactivation represents a strategy exploited by the parasite to promote its survival.

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Section: Discussionsupporting

confidence: 88%

Infection by the Protozoan Parasite Toxoplasma gondii Inhibits Host MNK1/2-eIF4E Axis to Promote Its Survival

Leroux

Chaparro

Jaramillo

2020

Front. Cell. Infect. Microbiol.

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“…Their functions and experimental targeting approaches are detailed in the tabular representation, respectively. (6) Ca 2+ influx sets the cell in a hypermotile state by activation of MAP kinases and cytoskeletal rearrangements ( Ólafsson et al, 2020 ). In the tabular representation, ( a ) Red colored text indicates molecular components commonly expressed by mouse and human phagocytes.…”

Section: Discussionmentioning

confidence: 99%

A motogenic GABAergic system of mononuclear phagocytes facilitates dissemination of coccidian parasites

Bhandage

Olivera

Kanatani

et al. 2020

eLife

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Gamma-aminobutyric acid (GABA) serves diverse biological functions in prokaryotes and eukaryotes, including neurotransmission in vertebrates. Yet, the role of GABA in the immune system has remained elusive. Here, a comprehensive characterization of human and murine myeloid mononuclear phagocytes revealed the presence of a conserved and tightly regulated GABAergic machinery with expression of GABA metabolic enzymes and transporters, GABA-A receptors and regulators, and voltage-dependent calcium channels. Infection challenge with the common coccidian parasites Toxoplasma gondii and Neospora caninum activated GABAergic signaling in phagocytes. Using gene silencing and pharmacological modulators in vitro and in vivo in mice, we identify the functional determinants of GABAergic signaling in parasitized phagocytes and demonstrate a link to calcium responses and migratory activation. The findings reveal a regulatory role for a GABAergic signaling machinery in the host-pathogen interplay between phagocytes and invasive coccidian parasites. The co-option of GABA underlies colonization of the host by a Trojan horse mechanism.

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“…When actively invaded by T. gondii, DCs undergo cytoskeletal changes with redistribution of integrins, reminiscent of MAT in ECM [24][25][26]. This migratory activation-termed hypermotility [27] requires live intracellular parasites [25], does not rely on chemotaxis [28] and is instead mediated by non-canonical GABAergic signalling and MAP kinase activation [23,[29][30][31][32]. However, it has remained unknown how highly migratory parasitised DCs interact with polarised endothelium.…”

Section: Introductionmentioning

confidence: 99%

Integrin-dependent migratory switches regulate the translocation of Toxoplasma-infected dendritic cells across brain endothelial monolayers

Ross

Hoeve

Barragán

2021

Cell. Mol. Life Sci.

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Multiple cellular processes, such as immune responses and cancer cell metastasis, crucially depend on interconvertible migration modes. However, knowledge is scarce on how infectious agents impact the processes of cell adhesion and migration at restrictive biological barriers. In extracellular matrix, dendritic cells (DCs) infected by the obligate intracellular protozoan Toxoplasma gondii undergo mesenchymal-to-amoeboid transition (MAT) for rapid integrin-independent migration. Here, in a cellular model of the blood–brain barrier, we report that parasitised DCs adhere to polarised endothelium and shift to integrin-dependent motility, accompanied by elevated transendothelial migration (TEM). Upon contact with endothelium, parasitised DCs dramatically reduced velocities and adhered under both static and shear stress conditions, thereby obliterating the infection-induced amoeboid motility displayed in collagen matrix. The motility of adherent parasitised DCs on endothelial monolayers was restored by blockade of β1 and β2 integrins or ICAM-1, which conversely reduced motility on collagen-coated surfaces. Moreover, parasitised DCs exhibited enhanced translocation across highly polarised primary murine brain endothelial cell monolayers. Blockade of β1, β2 integrins, ICAM-1 and PECAM-1 reduced TEM frequencies. Finally, gene silencing of the pan-integrin-cytoskeleton linker talin (Tln1) or of β1 integrin (Itgb1) in primary DCs resulted in increased motility on endothelium and decreased TEM. Adding to the paradigms of leukocyte diapedesis, the findings provide novel insights in how an intracellular pathogen impacts the migratory plasticity of leukocytes in response to the cellular environment, to promote infection-related dissemination.

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Convergent Met and voltage-gated Ca2+ channel signaling drives hypermigration of Toxoplasma-infected dendritic cells

Cited by 13 publications

References 60 publications

Infection by the Protozoan Parasite Toxoplasma gondii Inhibits Host MNK1/2-eIF4E Axis to Promote Its Survival

Infection by the Protozoan Parasite Toxoplasma gondii Inhibits Host MNK1/2-eIF4E Axis to Promote Its Survival

A motogenic GABAergic system of mononuclear phagocytes facilitates dissemination of coccidian parasites

Integrin-dependent migratory switches regulate the translocation of Toxoplasma-infected dendritic cells across brain endothelial monolayers

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