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Dual RNA-seq on pneumococcal infection to zebrafish embryo model

ABSTRACT: Zebrafish embryo has been emerging as an interesting model of infection due to their fecundity, transparency and availability of genetic tools. Streptococcus pneumoniae, the pneumococcus, is the main etiological agent of pneumonia, sepsis and meningitis. The bacteria expresses a very important virulence factor, pneumolysin able to form pores on cholesterol-based membranes and to activate innate immune system. Here, we exploited the recently described dual RNA-seq to simultaneously measure genome-wide expression of host and pathogen eight hours into infection. Functional enrichment analysis showed certain pathways such as autophagy and apoptosis being activated in the host while stress responses including pneumococcal competence. The study is the first to describe dual RNA-seq application in whole organism sequencing in infection model.

ORGANISM(S): Streptococcus pneumoniae Danio rerio

PROVIDER: GSE123988 | GEO | 2021/12/14

REPOSITORIES: GEO

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Transcription profiling by array of pneumococcal virulence factors expressed during meningitis in mice

Project description:Streptococcus pneumoniae is the most common cause of severe bacterial meningitis in children, the elderly, and immunocompromised individuals. To identify virulence factors preferentially expressed during meningitis, we conducted niche-specific genome-wide in vivo transcriptomic analysis after intranasal infection of mice with serotype 4 or 6A pneumococci. The expression of 34 bacterial genes was substantially altered in brain tissue of mice infected with either of the 2 strains. Ten upregulated genes were common to both strains, 7 of which were evaluated for their role in the development of meningitis. One previously uncharacterized protein, alpha-glycerophosphate oxidase (GlpO), was cytotoxic for human brain microvascular endothelial cells (HBMECs) via generation of H2O2. A glpO deletion mutant was defective in adherence to HBMECs in vitro as well as in progression from the blood to the brain in vivo. Mutant bacteria also induced markedly reduced meningeal inflammation and brain pathology compared with WT, despite similar levels of bacteremia. Immunization of mice with GlpO protected against invasive pneumococcal disease and provided additive protection when formulated with pneumolysin toxoid. Our results provide the basis of a strategy that can be adapted to identify genes that contribute to the development of meningitis caused by other pathogens. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-130]

2012-04-10 | E-BUGS-130 | biostudies-arrayexpress

Time-resolved dual RNA-seq reveals extensive rewiring of lung epithelial and pneumococcal transcriptomes during early infection

Project description:BACKGROUND: Streptococcus pneumoniae, the pneumococcus, is the main etiological agent of pneumonia. Pneumococcal infection is initiated by bacterial adherence to lung epithelial cells. The exact transcriptional changes occurring in both host and microbe during infection are unknown. Here, we developed a time-resolved infection model of human lung alveolar epithelial cells by S. pneumoniae and assess the resulting transcriptome changes in both organisms simultaneously by using dual RNA-seq. RESULTS: Functional analysis of the time-resolved dual RNA-seq data identifies several features of pneumococcal infection. For instance, we show that the glutathione-dependent reactive oxygen detoxification pathway in epithelial cells is activated by reactive oxygen species produced by S. pneumoniae. Addition of the antioxidant resveratrol during infection abates this response. At the same time, pneumococci activate the competence regulon during co-incubation with lung epithelial cells. By comparing transcriptional changes between wild-type encapsulated and mutant unencapsulated pneumococci, we demonstrate that adherent pneumococci, but not free-floating bacteria, repress innate immune responses in epithelial cells including expression of the chemokine IL-8 and the production of antimicrobial peptides. We also show that pneumococci activate several sugar transporters in response to adherence to epithelial cells and demonstrate that this activation depends on host-derived mucins. CONCLUSIONS: We provide a dual-transcriptomics overview of early pneumococcal infection in a time-resolved manner, providing new insights into host-microbe interactions. To allow easy access to the data by the community, a web-based platform was developed ( http://dualrnaseq.molgenrug.nl ). Further database exploration may expand our understanding of epithelial-pneumococcal interaction, leading to novel antimicrobial strategies.

2016-08-26 | GSE79595 | GEO

Characterization of Pneumococcal Genes Involved in Bloodstream Invasion in a Mouse Model

2015-09-19 | GSE73217 | GEO

Transcription profiling of rat hippocampus and cortex in the time series of Pneumococcal Meningitis infection

Project description:The aim of this work is to describe the transcriptomic changes underlying the complex mechanisms of the host response to pneumococcal meningitis in a temporal and spatial context. For this purpose we evaluated the gene expression profile of the two brain structures predominantly affected by brain damage i.e. the cortex and the hippocampus at four different stages of the disease (24-, 72-, 240- and 624 hours post infection) using an infant rat model. <br><br>The first two timepoints represent the acute and late disease phase of bacterial meningitis (BM) and 10 and 26days the recovery phase. At each timepoint 6 infected and 6 sham infected animals were sacrificed. Control and infected animals were age matched to avoid differences in the gene expression patterns due to developmental processes in the infant rat brain.

2010-02-24 | E-MEXP-1656 | biostudies-arrayexpress

Characterization of Pneumococcal Genes Involved in Bloodstream Invasion in a Mouse Model

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2015-09-19 | E-GEOD-73217 | biostudies-arrayexpress

Dual RNAseq of pneumococcal infection

Project description:Dual RNAseq of pneumococcal infection

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Project description:Influenza A virus (IAV) predisposes individuals to secondary infections with the bacterium Streptococcus pneumoniae (the pneumococcus). Infections may manifest as pneumonia, sepsis, meningitis or otitis media (OM). It remains controversial as to whether secondary pneumococcal disease is due to the induction of an aberrant immune response or IAV induced immunosuppression. Moreover, as the majority of studies have been performed in the context of pneumococcal pneumonia, it remains unclear how far these findings can be extrapolated to other pneumococcal disease phenotypes. Here, we demonstrate that the viral hemagglutinin (HA) mediates bacterial OM by inducing a pro-inflammatory response in the middle ear cavity in a replication-dependent manner. Importantly, our findings show that it is the inflammatory response that mediates pneumococcal replication; not viral suppression of the immune system or epithelial damage. This study provide the first evidence that HA induced inflammation drives pneumococcal replication in the middle ear cavity, which has important consequences to the treatment of pneumococcal OM.

2013-01-01 | GSE41098 | GEO

Bacteria hijack a neuro-immune axis in meninges to facilitate brain invasion

Project description:The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache. How pain and neuro-immune interactions impact meningeal host defenses is unclear. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system (CNS), affecting over one million people a year. Here we find that Nav1.8+ neuron signaling to immune cells in the meninges via the neuropeptide calcitonin gene-related peptide (CGRP) exacerbates bacterial meningitis. Nociceptor ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors via Pneumolysin to release CGRP, which acts through its receptor RAMP1 on meningeal macrophages to inhibit chemokine expression, neutrophil recruitment and antimicrobial defenses. Macrophage-specific RAMP1 deficiency or blockade of RAMP1 signaling enhanced immune responses and bacterial clearance in meninges and brain. Therefore, targeting a neuro-immune axis in the meninges can enhance host defenses and may be a potential treatment for bacterial meningitis.

2022-12-23 | GSE221681 | GEO

Genome-wide identification of Streptococcus pneumoniae genes essential for the development of experimental meningitis

Project description:We applied genomic array footprinting (GAF) in the search for genes of S. pneumoniae essential during the establishment and progression of experimental meningitis. Four libraries with a total of 6,000 independent TIGR4 marinerT7 transposon mutants were injected intra-cisternally in rabbits, and cerebrospinal fluid (CSF) was collected after three, nine, and fifteen hours. Microarray analysis of mutant-specific probes from CSF samples and inocula identified 82 genes of which mutants had become attenuated and eleven genes of which mutants had become enriched during infection. Screening results particularly point to an essential role for capsular polysaccharides (cps), nutrient uptake, and metabolism in meningitis. Detailed study on directed mutants of a subset of sixteen GAF targets in an experimental model of rat meningitis revealed that ten were significantly attenuated or enriched during competitive infection. Furthermore, we showed that mutants of adenylosuccinate synthetase (purA), flavodoxin (fld), and the substrate binding protein (livJ) of a branched chain amino acid ABC-transporter were essential for full blown meningitis in a mono-infection setup of rat meningitis. Overall, the GAF screen revealed the general restraint on nutrients encountered by the pneumococcus in CSF, while, except for cps genes, no ‘classic’ virulence factors appeared to be required for infection. This knowledge will contribute to a better understanding of the molecular pathogenesis of pneumococcal meningitis.

2010-11-16 | GSE21729 | GEO

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Project description:Our understanding of the synergism between S. pneumoniae and influenza virus remains incomplete. The classic dogma has been that influenza attenuates the host innate immunity and increase the susceptibility to subsequent bacterial infection. Therefore, the majority of current studies have been focusing on the interaction of S. pneumoniae and influenza in the context of host cells. By contrast, in this study, we set out to investigate the response of pneumococcus alone to virus infection. Our hypothesis was that prior to causing any damages to host cells, influenza may have induced (lethal) changes to pneumococcus cell itself. Indeed, a very recent evidence has shown that direct viral treatment to pneumococcus will increase its adhesion to macrophage cells. Here, using quantitative shotgun approach, we attempt to investigate the proteomic alterations of S. pneumoniae by influenza virus challenge, and provide a landscape of interactions between the IAV and pneumococcus.

2022-12-09 | PXD016122 | Pride

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