Correction: Irf8-regulated genomic responses drive pathological inflammation during cerebral malaria.
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ABSTRACT:
SUBMITTER: PLOS Pathogens Staff
PROVIDER: S-EPMC4349701 | biostudies-literature | 2015 Mar
REPOSITORIES: biostudies-literature
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Correction: Irf8-regulated genomic responses drive pathological inflammation during cerebral malaria.
PLoS pathogens 20150304 3
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Project description:Interferon Regulatory Factor 8 (IRF8) is required for development, maturation and expression of anti-microbial defenses of myeloid cells. BXH2 mice harbor a severely hypomorphic allele at Irf8 (Irf8(R294C)) that causes susceptibility to infection with intracellular pathogens including Mycobacterium tuberculosis. We report that BXH2 are completely resistant to the development of cerebral malaria (ECM) following Plasmodium berghei ANKA infection. Comparative transcriptional profiling of brain RNA as well as chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) was used to identify IRF8-regulated genes whose expression is associated with pathological acute neuroinflammation. Genes increased by infection were strongly enriched for IRF8 binding sites, suggesting that IRF8 acts as a transcriptional activator in inflammatory programs. These lists were enriched for myeloid-specific pathways, including interferon responses, antigen presentation and Th1 polarizing cytokines. We show that inactivation of several of these downstream target genes (including the Irf8 transcription partner Irf1) confers protection against ECM. ECM-resistance in Irf8 and Irf1 mutants is associated with impaired myeloid and lymphoid cells function, including production of IL12p40 and IFNγ. We note strong overlap between genes bound and regulated by IRF8 during ECM and genes regulated in the lungs of M. tuberculosis infected mice. This IRF8-dependent network contains several genes recently identified as risk factors in acute and chronic human inflammatory conditions. We report a common core of IRF8-bound genes forming a critical inflammatory host-response network.
| S-EPMC3708918 | biostudies-literature
Project description:Analysis of transcriptional response to Plasmodium berghei ANKA infection in cerebral malaria susceptible C57BL/6 mouse brains as well as cerebral malaria resistant BXH2 mice which carry a severe hypomorphic Irf8-R294C allele. Interferon Regulatory Factor 8 (IRF8) is required for development, maturation and expression of anti-microbial defenses of myeloid cells. BXH2 mice harbor a loss-of-function allele at Irf8 (Irf8-R294C) that causes susceptibility to infection with intracellular pathogens, including Mycobacterium tuberculosis. We report that XH2 are completely resistant to the development of cerebral malaria following Plasmodium berghei ANKA infection. Comparative transcriptional profiling of brain RNA as well as chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) was used to identify IRF8-regulated genes whose expression is associated with pathological acute neuroinflammation. Genes up-regulated by infection were strongly enriched for IRF8 binding sites, suggesting that IRF8 acts as a transcriptional activator in inflammatory programs. These lists were enriched for myeloid-specific pathways, including interferon responses, antigen presentation and Th1 polarizing cytokines. We show that inactivation of several of these downstream target genes confers protection against experimental cerebral malaria. We also report strong overlap between genes bound and regulated by IRF8 during cerebral malaria and genes regulated in the lungs of M. tuberculosis infected mice. This IRF8-dependent network contains several genes recently identified as risk factors in acute and chronic human inflammatory conditions. In summary, this work defines a common core of IRF8-bound genes forming a critical inflammatory host-response network. Comparison of whole brain transcript profiles for wildype C57BL/6 mice versus severely hypomorphic Irf8-R294C BXH2 mice following experimental infection with Plasmodium berghei ANKA (d7). Baseline (d0) profiles are also compared. Pleaes note that each sample record represents 2-4 replicates and sample data table contains mean, standard error of the mean (SEM), and quality for the replicates. The non_normalized data matrix contains raw data for each replicate (total 12 samples).
2015-01-16 | E-GEOD-65036 | biostudies-arrayexpress
Project description:Analysis of transcriptional response to Plasmodium berghei ANKA infection in cerebral malaria susceptible C57BL/6 mouse brains as well as cerebral malaria resistant BXH2 mice which carry a severe hypomorphic Irf8-R294C allele. Interferon Regulatory Factor 8 (IRF8) is required for development, maturation and expression of anti-microbial defenses of myeloid cells. BXH2 mice harbor a loss-of-function allele at Irf8 (Irf8-R294C) that causes susceptibility to infection with intracellular pathogens, including Mycobacterium tuberculosis. We report that XH2 are completely resistant to the development of cerebral malaria following Plasmodium berghei ANKA infection. Comparative transcriptional profiling of brain RNA as well as chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) was used to identify IRF8-regulated genes whose expression is associated with pathological acute neuroinflammation. Genes up-regulated by infection were strongly enriched for IRF8 binding sites, suggesting that IRF8 acts as a transcriptional activator in inflammatory programs. These lists were enriched for myeloid-specific pathways, including interferon responses, antigen presentation and Th1 polarizing cytokines. We show that inactivation of several of these downstream target genes confers protection against experimental cerebral malaria. We also report strong overlap between genes bound and regulated by IRF8 during cerebral malaria and genes regulated in the lungs of M. tuberculosis infected mice. This IRF8-dependent network contains several genes recently identified as risk factors in acute and chronic human inflammatory conditions. In summary, this work defines a common core of IRF8-bound genes forming a critical inflammatory host-response network.
2015-01-16 | GSE65036 | GEO
Project description:IntroductionA vaccine for malaria is urgently required but no vaccine has yet shown satisfactory protective efficacy especially for Plasmodium falciparum. P. falciparum infection can progress to cerebral malaria (CM), a neurological syndrome with exceedingly high mortality. Designing effective P. falciparum vaccines require more understanding of the protective immune response while the host immune response to CM and the mechanisms are still elusive. Here, we aim to identify host gene responses to CM and host gene networks associated with CM pathogenesis.MethodsAn innovative genomic analysis strategy, the weighted gene coexpression network analysis (WGCNA) combined with differential gene expression analysis, was used in this study. Data for analysis contain 93 whole blood samples, derived from two previous public transcriptome datasets.ResultsThis approach led to the identification of numerous differentially expressed human transcripts and dozens of coexpression gene modules. We further identified nine key genes, including MBP, SAMSN1, PSMF1, SLC39A8, EIF3B, SMPDL3A, FABP5, SPSB3, and SHARPIN, of which the last four genes were first identified to be related to CM in the present study.ConclusionThe results provided a comprehensive characterization of host gene expression profiles in CM and offered some new insight into malaria vaccine design. These identified key genes could be potential targets or immune modulators for novel therapeutic interventions of CM.
| S-EPMC8342194 | biostudies-literature
Project description:Interferon regulatory factor 8 (IRF8) is known to affect the innate immune response, for example, by regulating the differentiation and function of immune cells. However, whether IRF8 can influence cardiac hypertrophy is unknown. Here we show that IRF8 levels are decreased in human dilated/hypertrophic cardiomyopathic hearts and in murine hypertrophic hearts. Mice overexpressing Irf8 specifically in the heart are resistant to aortic banding (AB)-induced cardiac hypertrophy, whereas mice lacking IRF8 either globally or specifically in cardiomyocytes develop an aggravated phenotype induced by pressure overload. Mechanistically, we show that IRF8 directly interacts with NFATc1 to prevent NFATc1 translocation and thus inhibits the hypertrophic response. Inhibition of NFATc1 ameliorates the cardiac abnormalities in IRF8(-/-) mice after AB. In contrast, constitutive activation of NFATc1 nullifies the protective effects of IRF8 on cardiac hypertrophy in IRF8-overexpressing mice. Our results indicate that IRF8 is a potential therapeutic target in pathological cardiac hypertrophy.
| S-EPMC3929801 | biostudies-literature
Project description:Cerebral malaria (CM) is a major complication of Plasmodium falciparum infection in children. The pathogenesis of CM involves vascular inflammation, immune stimulation, and obstruction of cerebral capillaries. Platelets have a prominent role in both immune responses and vascular obstruction. We now demonstrate that the platelet-derived chemokine, platelet factor 4 (PF4)/CXCL4, promotes the development of experimental cerebral malaria (ECM). Plasmodium-infected red blood cells (RBCs) activated platelets independently of vascular effects, resulting in increased plasma PF4. PF4 or chemokine receptor CXCR3 null mice had less severe ECM, including decreased T cell recruitment to the brain, and platelet depletion or aspirin treatment reduced the development of ECM. We conclude that Plasmodium-infected RBCs can directly activate platelets, and platelet-derived PF4 then contributes to immune activation and T cell trafficking as part of the pathogenesis of ECM.
| S-EPMC2603442 | biostudies-literature
Project description:Sequestration of Plasmodium falciparum-infected erythrocytes (IEs) in the brain microcirculation is a hallmark of cerebral malaria (CM), which leads to endothelial activation, brain swelling, and death. Here, we probed CM inflammation in a perfusable 3D human brain microvessel model. 3D brain microvessels supported in vivo-like capacities for parasite binding and maturation in situ, leading to a distinct inflammatory response from the pro-inflammatory cytokine tumor necrosis factor α (TNF-α). By combining transcriptional analysis, imaging, and leukocyte perfusion, we showed that whereas TNF-α promotes a reversible inflammatory phenotype with widespread leukocyte recruitment, parasites induce unique stress response pathways and cause localized cell adhesivity changes, focal endothelial disruptions, and apoptosis. Furthermore, parasites modified the temporal kinetics of the TNF transcriptional response, suggesting augmented inflammatory damage with the two sequential stimuli. Our findings offer mechanistic insights into CM biology in a 3D brain microvessel mimetic platform and suggest that multiple events intersect to promote brain barrier inflammation in CM.
| S-EPMC10710687 | biostudies-literature
Project description:We hypothesized that differential gene expression contributes to phenotypic variation of parasites which results in specific interaction of Plasmodium falciparum with its human host. In this study we used microarray hybridization to analyse the transcriptomes of P.falciparum isolated from asymptomatic carriers and from cerebral and uncomplicated malaria patients. We also investigated the transcriptomes of the 3D7 clone and the selected 3D7-Lib line.
2014-12-01 | E-MTAB-2139 | biostudies-arrayexpress
Project description:Transient receptor potential vanilloid 1 (TRPV1) is a Ca+2-permeable channel expressed on neuronal and nonneuronal cells, known as an oxidative stress sensor. It plays a protective role in bacterial infection, and recent findings indicate that this receptor modulates monocyte populations in mice with malaria; however, its role in cerebral malaria progression and outcome is unclear. By using TRPV1 wild-type (WT) and knockout (KO) mice, the importance of TRPV1 to this cerebral syndrome was investigated. Infection with Plasmodium berghei ANKA decreased TRPV1 expression in the brain. Mice lacking TRPV1 were protected against Plasmodium-induced mortality and morbidity, a response that was associated with less cerebral swelling, modulation of the brain expression of endothelial tight-junction markers (junctional adhesion molecule A and claudin-5), increased oxidative stress (via inhibition of catalase activity and increased levels of H2O2, nitrotyrosine, and carbonyl residues), and diminished production of cytokines. Plasmodium load was not significantly affected by TRPV1 ablation. Repeated subcutaneous administration of the selective TRPV1 antagonist SB366791 after malaria induction increased TRPV1 expression in the brain tissue and enhanced mouse survival. These data indicate that TRPV1 channels contribute to the development and outcome of cerebral malaria.
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Project description: Not available
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