Abstract
The protozoan parasite Toxoplasma gondii modulates host cell responses to favor its success in the early stage of infections by secreting proteins from its apical organelles. Some of these proteins, including microneme proteins (MICs) 1 and 4, trigger pro-inflammatory host cell responses. The lectins MIC1 and MIC4 interact with N-linked glycans on TLR2 and TLR4, activating NF-κB and producing IL-12, TNF-α, and IL-6. Interestingly, MIC1 and MIC4 also trigger secretion of the anti-inflammatory cytokine IL-10 through mechanisms as yet unknown. Herein, we show that the ability of these MICs to induce macrophages to produce IL-10 depends on TLR4 internalization from the cell surface. Macrophages subjected to blockade of endocytosis by Dynasore continued to release TNF-α, but failed to produce IL-10, in response to MIC1 or MIC4 exposure. Similarly, IL-10 was not produced by Dynasore-conditioned T. gondii-infected macrophages. Furthermore, MIC1- or MIC4-stimulated macrophages gained transient tolerance to LPS. We report a previously undiscovered mechanism by which well-defined T. gondii components inhibit a host inflammatory response.
Highlights
Toxoplasma gondii is a protozoan obligate intracellular parasite of the phylum Apicomplexa, that causes toxoplasmosis
There was a significant decay in the presence of cell surface TLR4 over time, which was fastest on MIC1-stimulated cells, followed by similar rates on MIC4- and LPS-stimulated cells (Figure 1A)
To measure internalization of microneme protein/TLR4 complexes putatively formed on the cell surface, we performed quantitative analysis of complex component colocalization by confocal microscopy of bone marrow derived macrophages (BMDMs) stimulated with biotinylated MIC1 or MIC4 for 5, 10, and 15 min
Summary
Toxoplasma gondii is a protozoan obligate intracellular parasite of the phylum Apicomplexa, that causes toxoplasmosis. T. gondii infects a range of warm-blooded animals, including humans [1]. From the estimated 1/3 of the world’s population chronically infected with T. gondii, most of them are clinically asymptomatic. Reactivation of latent disease in immunocompromised patients frequently causes life-threatening encephalitis, and acute infection acquired during pregnancy can be fatal to the fetus [2,3,4]. T. gondii invades host cells via several mechanisms [5, 6], including recognition of carbohydrates on a host cell surface [7, 8]. The host cell response to contact with the parasite plays a crucial role in deciding infection outcome [9]
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