The UPR sensor IRE1? promotes dendritic cell responses to control Toxoplasma gondii infection.
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ABSTRACT:
SUBMITTER: Dr. Anais, F Poncet
PROVIDER: S-SCDT-EMBOR-2019-49617V1 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Host defense against the human pathogen Toxoplasma gondii depends on secretion of interferon (IFN)-γ and subsequent activation of monocytic cells to combat intracellular parasites. Previous studies have shown that T. gondii evades IFN-γ-mediated immunity by secreting the effector TgIST into the host cell where it binds to STAT1, strengthens its DNA binding activity and recruits the Mi-2/NuRD complex to STAT1-responsive promoters. Here we investigated the impact of the host chromatin environment on parasite interference with IFN-γ-induced gene expression. Luciferase reporters under control of primary and secondary IFN-γ response promoters were only inhibited by T. gondii when they were stably integrated into the host genome but not when expressed from a plasmid vector. Absence of CpG islands upstream and/or downstream of the transcriptional start site allowed more vigorous up-regulation by IFN-γ as compared to CpG-rich promoters. Remarkably, it also favored parasite interference with IFN-γ-induced gene expression indicating that nucleosome occupancy at IFN-γ-responsive promoters is important. Promoter DNA of IFN-γ-responsive genes remained largely non-methylated in T. gondii-infected cells, and inhibition of DNA methylation did not impact parasite interference with host responses. IFN-γ up-regulated histone marks H4ac, H3K9ac, and H3K4me3 but down-regulated H3S10p at primary and secondary response promoters. Infection with T. gondii abolished histone modification, whereas total nuclear activities of histone acetyl transferases and histone deacetylases were not altered. Taken together, our study reveals a critical impact of the host chromatin landscape at IFN-γ-activated promoters on their inhibition by T. gondii with a comprehensive blockade of histone modifications at parasite-inactivated promoters.
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Project description:BiP is a major endoplasmic reticulum (ER) chaperone and is suggested to act as primary sensor in the activation of the unfolded protein response (UPR). How BiP operates as a molecular chaperone and as an ER stress sensor is unknown. Here, by reconstituting components of human UPR, ER stress and BiP chaperone systems, we discover that the interaction of BiP with the luminal domains of UPR proteins IRE1 and PERK switch BiP from its chaperone cycle into an ER stress sensor cycle by preventing the binding of its co-chaperones, with loss of ATPase stimulation. Furthermore, misfolded protein-dependent dissociation of BiP from IRE1 is primed by ATP but not ADP. Our data elucidate a previously unidentified mechanistic cycle of BiP function that explains its ability to act as an Hsp70 chaperone and ER stress sensor.
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Project description:It was previously demonstrated that immunizing mice with spleen dendritic cells (DCs) that had been pulsed ex vivo with Toxoplasma gondii antigens triggers a systemic Th1-biased specific immune response and induces protection against infection. T. gondii can cause severe sequelae in the fetuses of mothers who acquire the infection during pregnancy, as well as life-threatening neuropathy in immunocompromised patients, in particular those with AIDS. Here, we investigate the efficacy of a novel cell-free vaccine composed of DC exosomes, which are secreted antigen-presenting vesicles that express functional major histocompatibility complex class I and II and T-cell-costimulatory molecules. They have already been shown to induce potent antitumor immune responses. We investigated the potential of DC2.4 cell line-derived exosomes to induce protective immunity against toxoplasmosis. Our data show that most adoptively transferred T. gondii-pulsed DC-derived exosomes were transferred to the spleen, elicited a strong systemic Th1-modulated Toxoplasma-specific immune response in vivo, and conferred good protection against infection. These findings support the possibility that DC-derived exosomes can be used for T. gondii immunoprophylaxis and for immunoprophylaxis against many other pathogens.
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Project description:We determined the association between Toxoplasma gondii (T. gondii) infection and insomnia. Through an age-and gender-matched case-control study, 577 people with insomnia (cases) and 577 people without insomnia (controls) were tested for anti-T. gondii IgG and IgM antibodies using commercially available enzyme-immunoassays. Anti-T. gondii IgG antibodies were found in 71 (12.3%) of 577 individuals with insomnia and in 46 (8.0%) of 577 controls (OR = 1.62; 95% CI: 1.09-2.39; P = 0.01). Men with insomnia had a higher (16/73: 21.9%) seroprevalence of T. gondii infection than men without insomnia (5/73: 6.8%) (OR: 3.81; 95% CI: 1.31-11.06; P = 0.009). The rate of high (>150 IU/ml) anti-T. gondii IgG antibody levels in cases was higher than the one in controls (OR = 2.21; 95% CI: 1.13-4.31; P = 0.01). Men with insomnia had a higher (8/73: 11.0%) rate of high anti-T. gondii IgG antibody levels than men without insomnia (0/73: 0.0%) (P = 0.006). The rate of high anti-T. gondii IgG antibody levels in cases >50 years old (11/180: 6.1%) was higher than that (3/180: 1.7%) in controls of the same age group (OR: 3.84; 95% CI: 1.05-14.00; P = 0.05). No difference in the rate of IgM seropositivity between cases and controls was found (OR = 1.33; 95% CI: 0.57-3.11; P = 0.50). Results of this seroepidemiology study suggest that infection with T. gondii is associated with insomnia. Men older than 50 years with T. gondii exposure might be prone to insomnia. Further research to confirm the association between seropositivity and serointensity to T. gondii and insomnia is needed.
| S-EPMC9182222 | biostudies-literature
Project description:BackgroundWomen in early pregnancy infected by Toxoplasma gondii may have severe adverse pregnancy outcomes, such as spontaneous abortion and fetal malformation. The inhibitory molecule T cell immunoglobulin and mucin domain 3 (Tim-3) is highly expressed on decidual dendritic cells (dDCs) and plays an important role in maintaining immune tolerance. However, whether T. gondii infection can cause dDC dysfunction by influencing the expression of Tim-3 and further participate in adverse pregnancy outcomes is still unclear.MethodsAn abnormal pregnancy model in Tim-3-deficient mice and primary human dDCs treated with Tim-3 neutralizing antibodies were used to examine the effect of Tim-3 expression on dDC dysfunction after T. gondii infection.ResultsFollowing T. gondii infection, the expression of Tim-3 on dDCs was downregulated, those of the pro-inflammatory functional molecules CD80, CD86, MHC-II, tumor necrosis factor-α (TNF-α), and interleukin-12 (IL-12) were increased, while those of the tolerant molecules indoleamine 2,3-dioxygenase (IDO) and interleukin-10 (IL-10) were significantly reduced. Tim-3 downregulation by T. gondii infection was closely associated with an increase in proinflammatory molecules and a decrease in tolerant molecules, which further resulted in dDC dysfunction. Moreover, the changes in Tim-3 induced by T. gondii infection further reduced the secretion of the cytokine IL-10 via the SRC-signal transducer and activator of transcription 3 (STAT3) pathway, which ultimately contributed to abnormal pregnancy outcomes.ConclusionsToxoplasma gondii infection can significantly downregulate the expression of Tim-3 and cause the aberrant expression of functional molecules in dDCs. This leads to dDC dysfunction, which can ultimately contribute to abnormal pregnancy outcomes. Further, the expression of the anti-inflammatory molecule IL-10 was significantly decreased by Tim-3 downregulation, which was mediated by the SRC-STAT3 signaling pathway in dDCs after T. gondii infection.
| S-EPMC9615254 | biostudies-literature
Project description:After oral infection, Toxoplasma gondii invades intestinal cells, induces breakdown of intestinal physiology and barrier functions, and causes intestinal pathology in some animal species. Although parasites' invasion into host cells is a known phenomenon, the effects of T. gondii infection in the intestinal barrier are still not well established. To evaluate morphological and physiological modifications on the colorectal adenocarcinoma-derived Caco-2 cell line during T. gondii infection, microvilli, tight junction integrity, and transepithelial electrical resistance (TEER) were investigated under infection. It was observed that the dextran uptake (endocytosis) and distribution were smaller in infected than in noninfected Caco-2 cells. The infection leads to the partial loss of microvilli at the cell surface. Claudin-1, zonula occludens-1 (ZO-1), and occludin expressions were colocalized by immunofluorescence and presented discontinuous net patterns in infected cells. Immunoblotting analysis at 24 hr postinfection revealed decreasing expression of occludin and ZO-1 proteins, whereas claudin-1 presented similar expression level compared with noninfected cells. T. gondii decreased TEER in Caco-2 cells 24 hr after infection. Our results suggest that T. gondii infection may lead to the loss of integrity of intestinal mucosa, resulting in impaired barrier function.
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Project description:Proteostasis of the endoplasmic reticulum (ER) is controlled by sophisticated signaling pathways that are collectively called the unfolded protein response (UPR) and are initiated by specialized ER membrane-associated sensors. The evidence that complete loss-of-function mutations of the most conserved of the UPR sensors, inositol-requiring enzyme 1 (IRE1), dysregulates tissue growth and development in metazoans and plants raises the fundamental question as to how IRE1 is connected to organismal growth. To address this question, we interrogated the Arabidopsis primary root, an established model for organ development, using the tractable Arabidopsis IRE1 mutant ire1a ire1b, which has marked root development defects in the absence of exogenous stress. We demonstrate that IRE1 is required to reach maximum rates of cell elongation and root growth. We also established that in the actively growing ire1a ire1b mutant root tips the Target of Rapamycin (TOR) kinase, a widely conserved pro-growth regulator, is hyperactive, and that, unlike cell proliferation, the rate of cell differentiation is enhanced in ire1a ire1b in a TOR-dependent manner. By functionally connecting two essential growth regulators, these results underpin a novel and critical role of IRE1 in organ development and indicate that, as cells exit an undifferentiated state, IRE1 is required to monitor TOR activity to balance cell expansion and maturation during organ biogenesis.
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Project description:To better understand the initiation of CD8(+) T cell responses during infection, the primary response to the intracellular parasite Toxoplasma gondii was characterized using 2-photon microscopy combined with an experimental system that allowed visualization of dendritic cells (DCs) and parasite specific CD8(+) T cells. Infection with T. gondii induced localization of both these populations to the sub-capsular/interfollicular region of the draining lymph node and DCs were required for the expansion of the T cells. Consistent with current models, in the presence of cognate antigen, the average velocity of CD8(+) T cells decreased. Unexpectedly, infection also resulted in modulation of the behavior of non-parasite specific T cells. This TCR-independent process correlated with the re-modeling of the lymph node micro-architecture and changes in expression of CCL21 and CCL3. Infection also resulted in sustained interactions between the DCs and CD8(+) T cells that were visualized only in the presence of cognate antigen and were limited to an early phase in the response. Infected DCs were rare within the lymph node during this time frame; however, DCs presenting the cognate antigen were detected. Together, these data provide novel insights into the earliest interaction between DCs and CD8(+) T cells and suggest that cross presentation by bystander DCs rather than infected DCs is an important route of antigen presentation during toxoplasmosis.
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Project description:Dysregulation of inositol-requiring enzyme 1 (IRE1), the primary transducer of Unfolded Protein Response (UPR), has been observed in tumor initiation and progression, but the underlying mechanism remains to be further elucidated. In this study, we identified that the IRE1 gene is frequently amplified and over-expressed in aggressive luminal B breast cancer cells and that IRE1 upregulation is significantly associated with worse overall survival of patients with breast cancer. IRE1 processes and mediates degradation of a subset of tumor suppressor microRNAs (miRNAs), including miR-3607, miR-374a, and miR-96, via a mechanism called Regulated IRE1-Dependent Decay (RIDD). IRE1-dependent degradation of tumor suppressor miR-3607 leads to elevation of RAS oncogene GTPase RAB3B in breast cancer cells. Inhibition of IRE1 endoribonuclease activity with the pharmacological compound 4μ8C or genetic approaches effectively suppresses luminal breast cancer cell proliferation and aggressive cancer phenotypes. Our work revealed the IRE1-RIDD-miRNAs pathway that promotes malignancy of luminal breast cancer.
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