The Protozoan Parasite Toxoplasma gondii Selectively Reprograms the Host Cell Translatome

Abstract

The intracellular parasite promotes infection by targeting multiple host cell processes; however, whether it modulates mRNA translation is currently unknown. Here, we show that infection of primary murine macrophages with type I or II strains causes a profound perturbation of the host cell translatome. Notably, translation of transcripts encoding proteins involved in metabolic activity and components of the translation machinery was activated upon infection. In contrast, the translational efficiency of mRNAs related to immune cell activation and cytoskeleton/cytoplasm organization was largely suppressed. Mechanistically, bolstered mechanistic target of rapamycin (mTOR) signaling to selectively activate the translation of mTOR-sensitive mRNAs, including those with a 5'-terminal oligopyrimidine (5' TOP) motif and those encoding mitochondrion-related proteins. Consistent with parasite modulation of host mTOR-sensitive translation to promote infection, inhibition of mTOR activity suppressed replication. Thus, selective reprogramming of host mRNA translation represents an important subversion strategy during infection.

Leishmania donovani Lipophosphoglycan Increases Macrophage-Dependent Chemotaxis of CXCR6-Expressing Cells via CXCL16 Induction

“…3D). Note that these compounds do not exert toxic effects on BMDM up to 24 h, as we previously described (45). Thus, these data provide evidence that L. donovani induces the expression of CXCL16 in macrophages via AKT/mTOR-dependent and TLR-independent mechanisms.…”

“…These results suggest that in addition to transcription, L. donovani might enhance the stability and/or the translation efficiency of Cxcl16 mRNA. Of note, we recently demonstrated that another protozoan parasite, Toxoplasma gondii, selectively regulates translation of immune-related transcripts in macrophages via the mTOR complex 1 (mTORC1), including chemokines (45). Therefore, sustained mTOR activity during L. donovani infection might be required to upregulate CXCL16 expression through both transcriptional and posttranscriptional mechanisms.…”

“…Differentiation of BMDM. Bone marrow precursor cells were obtained from femurs and tibias of commercial C57BL/6J (The Jackson Laboratory), cxcl16 KO, unc93b KO, and myd88 KO mice and differentiated into bone marrow-derived macrophages (BMDM) as previously described (45). Briefly, bone marrow precursor cells were flushed from femurs and tibias maintained in HBSS (100 U/ml penicillin, 100 g/ml streptomycin, 4.2 mM sodium bicarbonate) at 4°C.…”

Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape

“…The type I and III strains of T. gondii associate with mitochondria during infection and this association impacts cytokine responses (including increased pro-inflammatory IL-6 and CCL5, but also anti-inflammatory IL-10 production) during in vitro infection of BMDMs with T. gondii and ex vivo in peritoneal exudate cells (PECs) isolated from infected C57BL/6 mice. Therefore, the mitochondrial association and translation of mitochondrial transcripts via mTOR could be a possible route for the manipulation of the host immune response by T. gondii [177,178].…”

Modulation of the mTOR pathway plays a central role in dendritic cell functions after Echinococcus granulosus antigen recognition

“…In our assays, we corroborated that the stimulation of BMDCs with pLL and HF did not cause a significant decrease in cell viability ( Figure 1A), thus both antigens were used for the subsequent studies. Recognition of parasite-derived molecules induced not only the production of specific genes like cytokines, co-stimulatory molecules, or the up-regulation of MHC; but also promoted the transcription and translation of hundreds of genes, in order to control infection 50,51 . In this sense, mTOR appears to be part of the early sensing machinery, bridging the gap between PRR signaling and the cellular metabolism required to organize and trigger an effective immune response.…”