Project description:We evaluated transcriptional profiles in peripheral blood mononuclear cells (PBMCs) from 54 pregnant women in Kenya, 19 of whom delivered preterm.
Project description:Pregnancy appears to accelerate mortality associated with infectious diseases; however, the underlying mechanism of the crosstalk between pregnancy and sepsis remains poorly understood. Integrated multiomics analysis of gut microbiome revealed that the abundances of Parabacteroides merdae and its-derived formononetin (FMN) were decreased during pregnancy. Here, we verified that gut microbiota dysbiosis during pregnancy exacerbated immune exhaustion caused by sepsis through accelerating macrophage pyroptosis. Mechanistically, FMN suppressed nucleus-accumulation of hnRNPUL2 to prevent it from binding to Nlrp3 promoter region, thus to inhibit priming of NLRP3 inflammasome. Genetic knockdown of murine hnRNPUL2 by an adeno-associated virus protected against sepsis. Intriguingly, the abundances of Parabacteroides merdae and FMN in feces were negatively correlated with the progression of septic patients. Our data highlighted the significance of FMN/hnRNPUL2/NLRP3 axis mediated by dysbiosis of Parabacteroides merdae in immune exhaustion of pregnant septic hosts, shedding light on promising therapeutic strategies for the treatment of sepsis.
Project description:Blood immunomonitoring uncovers pregnancy-induced immune programs and their dysregulation in lupus pregnancy destined for complications
Project description:Toxoplasma gondii (T. gondii) is an obligate intracellular parasite that can lead to adverse pregnancy outcomes, particularly in early pregnancy. Previous studies have illustrated the landscape of decidual immune cells. However, the landscape of decidual immune cells in the maternal–fetal microenvironment during T. gondii infection remains unknown. In this study, we employed single-cell RNA sequencing to analyze the changes in human decidual immune cells following T. gondii infection. Our results showed that the proportion of 17 decidual immune cell clusters and the expression levels of 21 genes were changed after T. gondii infection. Differential gene analysis demonstrated that T. gondii infection induced the differential expression of 279, 312, and 380 genes in decidual NK, dMφ, and dT cells, respectively. Our findings first revealed that several previously unknown molecules in decidual immune cells changed following T. gondii infection. This result revealed that the function of maternal–fetal immune tolerance declined, whereas the killing ability of decidual immune cells enhanced, eventually contributing to the occurrence of adverse pregnancy outcomes. The results of this study provide a valuable resource for uncovering several novel molecules that play an important role in the occurrence of abnormal pregnancy outcomes induced by T. gondii infection.
Project description:Metabolic heterogeneity is a determinant of immune cell function. The normal physiological metabolic reprogramming of pregnancy that ensures the fuel requirements of mother and baby are met might also underpin changes in innate and adaptive immunity that occur with pregnancy and manifest as altered responses to pathogens and changes to autoimmune disease symptoms. Here, we use peripheral blood monocytes, susceptible to microenvironmentally determined reprogramming of metabolism, to determine if pregnancy at term provokes an altered metabolic profile that underpins functional change. Focusing on late gestation where any effect will be most profound, we reveal that monocytes lose M2-like and gain M1-like properties accompanied by reductions in mitochondrial mass, maximal respiration and cardiolipin content in pregnancy; glycolysis is unperturbed. We establish that muramyl dipeptide (MDP)-stimulated cytokine production relies on oxidative metabolism then show that reduced monocyte oxidative metabolism with pregnancy compromises the production of TNF and IL-6 in response to MDP but not LPS. Overall, mitochondrially centred metabolic capabilities of late gestation monocytes are downregulated revealing natural plasticity in monocyte phenotype and function that could reveal targets for improving pregnancy outcomes but also yield new therapeutic approaches to diverse metabolic and/or immune-mediated diseases beyond pregnancy.
Project description:Rationale: Maternal immune responses can promote allergy development in offspring. Pilot data show that neonates of mother mice exposed during pregnancy to air pollution particles have increased allergic susceptibility. Objective: We investigated whether inflammatory response to titanium dioxide (TiO2) particles earlier considered immunologically ‘inert’ is enhanced during pregnancy. Methods: Pregnant BALB/c mice (or non-pregnant controls) received particle suspensions intranasally at day 14 of pregnancy. Lung inflammatory responses were evaluated 19 and 48 h after exposure. Results: Pregnant mice showed robust and persistent acute inflammatory responses after exposure to TiO2, while non-pregnant females had the expected minimal responses. Genomic profiling identified genes differentially expressed in pregnant lungs exposed to TiO2. Neonates of mothers exposed to TiO2 (but not PBS) developed increased susceptibility to allergens. Conclusion: Pregnancy enhances lung inflammatory responses to otherwise relatively innocuous inert particles. Keywords: Particles exposure, pregnancy vs normal
Project description:Endometrial decidualization connecting embryo implantation and placentation is transient, but essential for successful pregnancy, which however is not systematically investigated. Here, by using a novel single-cell spatial transcriptomic profiling technology (scStereo-seq), we were able to visualize and define key and dynamic functional decidual hubs assembled by distinct immune, endothelial, trophoblast and decidual stromal cells (DSCs) during early pregnancy in mice. We classified DSC subclusters and described their transdifferentiation trajectory controlled by transcription factor cascades. Interestingly, we discovered a novel type of DSCs expressing immune cell-specific genes, termed immune DSCs (iDSCs). Whereas immature DSCs attracted immune cells and induced decidual angiogenesis at the mesenchymal-to-epithelial transition (MET) hub during decidualization initiation, iDSCs enabled immune cell recruitment, angiogenesis facilitation and cytotoxic effect induction to form immune cell assembling and angiogenesis hubs, which eventually allow decidual homeostasis maintenance and decidualization-to-placentation transition. We spatiotemporally decode mouse early pregnancy events controlled by immune DSCs.
Project description:Endometrial decidualization connecting embryo implantation and placentation is transient, but essential for successful pregnancy, which however is not systematically investigated. Here, by using a novel single-cell spatial transcriptomic profiling technology (scStereo-seq), we were able to visualize and define key and dynamic functional decidual hubs assembled by distinct immune, endothelial, trophoblast and decidual stromal cells (DSCs) during early pregnancy in mice. We classified DSC subclusters and described their transdifferentiation trajectory controlled by transcription factor cascades. Interestingly, we discovered a novel type of DSCs expressing immune cell-specific genes, termed immune DSCs (iDSCs). Whereas immature DSCs attracted immune cells and induced decidual angiogenesis at the mesenchymal-to-epithelial transition (MET) hub during decidualization initiation, iDSCs enabled immune cell recruitment, angiogenesis facilitation and cytotoxic effect induction to form immune cell assembling and angiogenesis hubs, which eventually allow decidual homeostasis maintenance and decidualization-to-placentation transition. We spatiotemporally decode mouse early pregnancy events controlled by immune DSCs.
Project description:Immune patterns in Ebola patients were characterized depending on the outcome of the illness. Non-healthy controls were compared to Ebola patients to define the specificity of the immune response against Ebola virus infection.
Project description:Exosomes are extracellular vesicles secreted by cells that have an important biological function in intercellular communication by transferring biologically active proteins, lipids, and RNAs to neighbouring or distant cells. While a role for exosomes in antimicrobial defence has recently emerged, currently very little is known regarding the nature and functional relevance of exosomes generated in vivo, particularly during an active viral infection. Here, we characterised exosomes released into the airways during influenza virus infection. We show that these vesicles dynamically change in protein composition over the course of infection, increasing expression of host proteins with known anti-influenza activity, and viral proteins with the potential to trigger host immune responses. We show that exosomes released into the airways during influenza virus infection trigger pulmonary inflammation and carry viral antigen that can be utilized by antigen presenting cells to drive the induction of a cellular immune response. Moreover, we show that attachment factors for influenza virus, namely α2,3 and α2,6-linked sialic acids, are present on the surface of airway exosomes and these vesicles have the ability to neutralize influenza virus, thereby preventing the virus from binding and entering target cells. These data reveal a novel role for airway exosomes in the antiviral innate immune defence against influenza virus infection.