Th1-mediated immune programming is protective during craniotomy infection
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1189518 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31449839.fastq.gz | Fastqsanger.gz | |||
| SRR31449840.fastq.gz | Fastqsanger.gz | |||
| SRR31449841.fastq.gz | Fastqsanger.gz | |||
| SRR31449842.fastq.gz | Fastqsanger.gz | |||
| SRR31449843.fastq.gz | Fastqsanger.gz |
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Project description:A craniotomy is a neurosurgical procedure performed to access the intracranial space. In 3-5% of cases, infection can develop, most commonly caused by Staphylococcus aureus biofilm formation on the surface of the skull. Medical management of this infection is difficult, as biofilm properties confer immune- and antimicrobial recalcitrance to the infection and necessitate additional surgical procedures. Still, treatment failure rates can be appreciably high. These factors, in conjunction with rapidly expanding rates of antibacterial resistance, necessitate the development of alternative treatment strategies targeting and reversing the dysfunctional immune response that develops during biofilm infection. Our recent work has identified Th1 and Th17 CD4+ T cells as potent regulators of innate immune antimicrobial capacity during craniotomy infection, where enhanced signatures of IFN-γ production and signaling were observed at the site of infection. Here, we follow up on these findings to determine the specific role of IFN-γ in programing the immune response to biofilm infection using global and cell-type-restricted IFN-γR deficient mice. We show exaggerated bacterial outgrowth in the absence of IFN-γR, despite few changes in immune cell recruitment relative to WT mice. Single-cell transcriptomic analysis identified candidate explanations for this phenotype as alterations in cell death pathways, innate immune cell activation, MHC-II expression, and CD4+ T cell skewing in IFN-γR KO mice. While PMN pyroptosis in vitro and macrophage/microglia MHC-II levels in vivo displayed sensitivity to IFN-γ signaling, granulocyte- and macrophage/microglia-specific conditional IFN-γR KO experiments isolated these factors from observed increases in bacterial burden. Instead, we uncovered evidence of a decreased Th1/Th17 ratio which was corroborated by elevated IL-17 levels during IFN-γR deficiency and correlated with dysfunctional cellular communication with the innate immune system. Further, Th17 cells were less effective than Th1 cells in stimulating macrophage and microglia bacterial killing. In sum, this work identifies Th1 cells as uniquely protective during craniotomy infection, where they likely enhance macrophage and microglial antibacterial abilities in an IFN-γ-independent manner. Therefore, augmentation of CD4+ T cell differentiation towards a Th1 bias may represent a novel therapeutic strategy for treating craniotomy infection in the future.
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Project description:Single cells RNA-Seq of CD45+ cells during Staphylococcus aureus craniotomy infection
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Project description:Induction of long-lived antibody responses during infection or vaccination is often essential for subsequent protection, but the relative contributions of T follicular helper (Tfh) cells and T helper 1 (Th1) cells for induction of antigen specific antibody responses to viruses are unclear. Here, we establish an acute Zika virus (ZIKV) infection model in immunocompetent mice, and show that ZIKV infection elicits robust Th1-like Tfh cell and protective antibody responses. While these Th1-like Tfh cells share phenotypic and transcriptomic profiles with both Tfh and Th1 cells, they also have unique surface markers and gene expression characteristics, and are dependent on T-bet for their development. Th1-like Tfh cells, but not Th1 cells, are essential for class switching of ZIKV-specific IgG2c antibodies and maintenance of long-term neutralizing antibody responses. Our study suggests that specific modulation of the Th1-like Tfh cell response during infection or vaccination may augment the induction of antiviral antibody response to ZIKV and other viruses.
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Project description:scRNA-seq of phagocytic vs. non phagocytic immune cells during acute S. aureus craniotomy infection
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Project description:Neurosurgeries complicated by bacterial infection are often associated with poor clinical prognosis and prolonged treatment strategies involving multiple surgeries, placing additional morbidity on an already fragile patient population. Craniotomy is one of the most common neurosurgical procedures with an infection rate of 1-7%; however, the cellular and molecular signatures associated with craniotomy infection in human subjects have not yet been investigated. We performed a retrospective study of over 2,500 craniotomies, which revealed diversity in patient demographics, pathogen identity, and surgical landscapes associated with infection. Leukocyte profiling in tissues procured from craniotomy infection patients revealed a predominance of granulocytic myeloid-derived suppressor cells (G-MDSCs), which were absent from the blood. Single-cell transcriptomics identified immunometabolic shifts in leukocytes invading infected tissues, including a prominent hypoxia-inducible factor-1 (HIF-1) signature, whereas peripheral blood cells from the same patient were largely quiescent. The importance of HIF-1 signaling was validated using a mouse model of Staphylococcus aureus craniotomy infection, where the local delivery of HIF-1 inhibitor microparticles attenuated proinflammatory cytokine production concomitant with a significant increase in leukocyte infiltrates into the infected brain and galea. These findings establish G-MDSCs as a major infiltrate during human craniotomy infection and identify conserved transcriptional signatures across several leukocyte populations that may represent promising therapeutic targets for craniotomy infection in the face of increasing antimicrobial resistance.
2024-05-09 | GSE249319 | GEO
Project description:Respiratory Syncytial Virus (RSV) is a leading cause of morbidity and mortality in children, due in part to their distinct immune system, characterized by impaired induction of T-helper 1 (Th1)‐immunity. Here we describe cationic adjuvant formulation (CAF)-08, a liposomal vaccine formulation tailored to induce Th1 immunity in early life via synergistic engagement of Toll-like Receptor 7/8 and the C-type lectin receptor Mincle. Quantitative phosphoproteomics applied to human dendritic cells revealed a key role for Protein Kinase C- for enhanced Th1 cytokine production in neonatal dendritic cells and identified signaling events resulting in antigen cross-presentation. In vivo, a single immunization at birth with CAF08-adjuvanted RSV pre-fusion antigen protected newborn mice from RSV infection through induction of antigen-specific CD8+ and Th1 cells. Overall, we describe a novel pediatric adjuvant formulation and characterize its mechanism of action providing a promising avenue for development of early life vaccines against RSV and other intracellular pathogens.
2022-06-14 | PXD025568 | Pride
Project description:Access to the brain for treating neurological sequalae requires a craniotomy, which can be complicated by infection. T cells preferentially home to the brain, but not other tissue sites, during Staphylococcus aureus (S. aureus) craniotomy infection; however, their functional importance is unknown. CD4+ T cells were critical for bacterial containment during craniotomy infection as Rag1-/- mice and WT animals treated with anti-CD4 or VLA-4 and LFA-1 antibodies exhibited elevated bacterial burdens. scRNA-seq revealed transcriptional heterogeneity in brain CD3+ infiltrates, with CD4+ cells most prominent and typified by both Th1 and Th17 signatures, and adoptive transfer of either subset in Rag1-/- mice prevented S. aureus outgrowth. scRNA-seq revealed a profound IFN-γ signature in innate immune cells from Rag1-/- mice during craniotomy infection, supporting extensive T cell-innate immune crosstalk that was validated by immunostaining in the brain parenchyma. A cooperative role for Th1 and Th17 driven responses was demonstrated by treatment of Ifng-/- mice with IL-17A/F neutralizing Ab that recapitulated phenotypes observed in Rag1-/- animals, which were not observed following the loss of either cytokine alone. Collectively, these results implicate a critical role for CD4+ T cells in S. aureus containment during craniotomy infection by shaping the innate immune landscape.
2024-11-25 | GSE264736 | GEO
Project description:Access to the brain for treating neurological sequalae requires a craniotomy, which can be complicated by infection. T cells preferentially home to the brain, but not other tissue sites, during Staphylococcus aureus (S. aureus) craniotomy infection; however, their functional importance is unknown. CD4+ T cells were critical for bacterial containment during craniotomy infection as Rag1-/- mice and WT animals treated with anti-CD4 or VLA-4 and LFA-1 antibodies exhibited elevated bacterial burdens. scRNA-seq revealed transcriptional heterogeneity in brain CD3+ infiltrates, with CD4+ cells most prominent and typified by both Th1 and Th17 signatures, and adoptive transfer of either subset in Rag1-/- mice prevented S. aureus outgrowth. scRNA-seq revealed a profound IFN-γ signature in innate immune cells from Rag1-/- mice during craniotomy infection, supporting extensive T cell-innate immune crosstalk that was validated by immunostaining in the brain parenchyma. A cooperative role for Th1 and Th17 driven responses was demonstrated by treatment of Ifng-/- mice with IL-17A/F neutralizing Ab that recapitulated phenotypes observed in Rag1-/- animals, which were not observed following the loss of either cytokine alone. Collectively, these results implicate a critical role for CD4+ T cells in S. aureus containment during craniotomy infection by shaping the innate immune landscape.
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Project description:Gene expression profiling of repeatedly activated compared to recently activated Th1 cells to identify genes that play a role in chronic inflammatory disorders and may qualify as diagnostic or therapeutic targets; ; Upon activation under appropriate costimulatory conditions, naive T helper (Th) cells differentiate into Th2 or Th17 cells, each characterized by the expression of specific effector cytokines. In response to a repeated stimulation with antigen, Th cells develop a stable memory for the expression of those cytokines as well as for other secreted or membrane-associated factors. The stable memory for the expression of proinflammatory effector functions may explain the resistance of Th effector cells to conventional immunosuppressive therapy, and the inability of immunosuppression to cure chronic inflammation. The imprinting of the functional memory is based on epigenetic modifications and expression of distinct transcription factors. In this project, we compare the transcriptomes of once and repeatedly activated murine Th1 cells, to identify genes that induce and maintain the functional memory and control the persistence of pathogenic memory Th1 cells. This in turn might help to discriminate pathogenic versus protective cells in immunopathology and present novel targets for the diagnosis and therapy of chronic inflammatory disease. Experiment Overall Design: Genes differentially expressed in once versus four times stimulated Th1 cells. In vitro polarization of murine naïve DO11.10 T cells towards Th1 direction (5 ng/ml recombinant murine IL-12, 5 μg/ml anti-IL-4 antibody) with antigenic stimulation (ova323-339 and irradiated splenic APCs). The transcriptional profiles of resting one week old Th1 (Th1 1w) cells and resting 4 week old Th1 (Th1 4w) cells were compared using Affymetrix Murine Genome (MG) U74V2A GeneChip arrays. Experiment Overall Design: 10 µg of total RNA from each cell sample was reverse transcribed using T7-(d)T24 primer and SuperScript II reverse transcriptase Experiment Overall Design: cDNA extraction with a PhaseLock gel (Eppendorf), and precipitation with ethanol and ammonium acetate Experiment Overall Design: Biotinylated cRNA was transcribed with the MEGAscript high yield transcription kit (Ambion), fragmented, and the hybridization cocktail was prepared (15 µg fragmented biotin-labeled cRNA spiked with Eukaryotic Hybridization control) Experiment Overall Design: probes were subsequently hybridised with the GeneChip U74Av2 for 16 hrs at 45 oC Experiment Overall Design: after washing the hybridisation signals were visualised by staining with streptavidin-phycoerythrin and amplification with an anti-streptavidin antibody Experiment Overall Design: TH1_1w_C1; TH1_1w_C2; TH1_1w_C3TH1_4w_C1; TH1_4w_C2; TH1_4w_C3 Experiment Overall Design: 1w: 1 week in culture; 4w: 4 weeks in culture; C1-3: Culture or Experiment No.
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