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A Scalable Gut Organoid Model Reveals the Genome-Wide Invasion Landscape of a Human-Adapted Pathogen [pilot_TraDIS]

ABSTRACT: Studying the pathogenesis of human-restricted microbes is challenging, since small animal models often fail to recapitulate human physiology and suffer from infection bottlenecks that confound genetic screens. Hence, the comprehensive genetic and regulatory circuits driving the infection process of major human pathogens like Shigella flexneri remain to be defined. We combined large-scale Shigella infections of enteroids and colonoids with Transposon Directed Insertion Sequencing (TraDIS) and Bayesian statistical modelling, thereby establishing the first genome-wide map of Shigella genes required to colonize human intestinal epithelium. Our study revealed the Shigella virulence effectors essential for epithelial cell invasion across geometries and intestinal segments, identified over 100 chromosomal genes involved in the process, and uncovered a post-transcriptional mechanism whereby tRNA modification enzymes exert global control of a bacterial virulence program. Our findings provide a broadly applicable framework for combining advanced organotypic tissue culture with computational tools to map human – microbe interactions at scale.

ORGANISM(S): Shigella flexneri

PROVIDER: GSE267397 | GEO | 2025/04/03

REPOSITORIES: GEO

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A Scalable Gut Organoid Model Reveals the Genome-Wide Invasion Landscape of a Human-Adapted Pathogen [pilot_RNAseq]

Project description:Studying the pathogenesis of human-restricted microbes is challenging, since small animal models often fail to recapitulate human physiology and suffer from infection bottlenecks that confound genetic screens. Hence, the comprehensive genetic and regulatory circuits driving the infection process of major human pathogens like Shigella flexneri remain to be defined. We combined large-scale Shigella infections of enteroids and colonoids with Transposon Directed Insertion Sequencing (TraDIS) and Bayesian statistical modelling, thereby establishing the first genome-wide map of Shigella genes required to colonize human intestinal epithelium. Our study revealed the Shigella virulence effectors essential for epithelial cell invasion across geometries and intestinal segments, identified over 100 chromosomal genes involved in the process, and uncovered a post-transcriptional mechanism whereby tRNA modification enzymes exert global control of a bacterial virulence program. Our findings provide a broadly applicable framework for combining advanced organotypic tissue culture with computational tools to map human – microbe interactions at scale.

2025-04-03 | GSE267395 | GEO

A Scalable Gut Organoid Model Reveals the Genome-Wide Invasion Landscape of a Human-Adapted Pathogen [TraDIS_screen]

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Role of PhoPQ TCS plays in Shigella virulence

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Detection of Q-modification in RNAs from S. pombe and S. flexneri via reverse transcription using RT-KTq I614Y (Q-MaP-Seq)

Project description:In most eukaryotes and bacteria, queuosine (Q) replaces the guanosine at the wobble position of tRNAs harboring a GUN anticodon. To faithfully detect Q-modification in RNAs from Schizosaccharomyces pombe and Shigella flexneri, Q-MaP-Seq was established and applied to tRNAs from S. pombe WT (AEP1) cells and Shigella flexneri WT cells and tgt∆ cells. Q-modification of in vitro-transcribed RNAs and RNAs isolated from S. pombe and S. flexneri followed by reverse transcription using the RT-active DNA polymerase variant RT-KTq I614Y and sequencing of unmodified compared to modified RNAs allowed identification of Q-sites within tRNAs.

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The expression profiles analysis of a virulence plasmid-cured strain of shigella flexneri

Project description:In this study, we analyzed the expression profiles of a virulence plasmid-cured strain and wild-type strain of shigella flexneri. The results showed that the genes of glp regulon were upregulated in mutant bacteria in stationary phase cultures.

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Dual RNA-seq of zebrafish larvae infected with Shigella sonnei

Project description:Shigella flexneri is historically regarded as the primary agent of bacillary dysentery, yet the closely-related Shigella sonnei is replacing S. flexneri, especially in developing countries. The underlying reasons for this dramatic shift are mostly unknown. Using a zebrafish (Danio rerio) model of Shigella infection, we discover that S. sonnei is more virulent than S. flexneri in vivo. Whole animal dual-RNAseq and testing of bacterial mutants suggest that S. sonnei virulence depends on its O-antigen oligosaccharide (which is unique among Shigella species). We show in vivo using zebrafish and ex vivo using human neutrophils that S. sonnei O-antigen can mediate neutrophil tolerance. Consistent with this, we demonstrate that O-antigen enables S. sonnei to resist phagolysosome acidification and promotes neutrophil cell death. Chemical inhibition or promotion of phagolysosome maturation respectively decreases and increases neutrophil control of S. sonnei and zebrafish survival. Strikingly, larvae primed with a sublethal dose of S. sonnei are protected against a secondary lethal dose of S. sonnei in an O-antigen-dependent manner, indicating that exposure to O-antigen can train the innate immune system against S. sonnei. Collectively, these findings reveal O-antigen as an important therapeutic target against bacillary dysentery, and may explain the rapidly increasing S. sonnei burden in developing countries.

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miRNA profiling of human colon cells infected with the bacterium Shigella flexneri

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LC-MS/MS of the secreted fraction of Shigella

Project description:Many human Gram-negative bacterial pathogens express a Type Three Secretion Apparatus (T3SA), including among the most notorious Shigella spp., Salmonella enterica, Yersinia enterocolitica and enteropathogenic Escherichia coli (EPEC). These bacteria express on their surface multiple copies of the T3SA that mediate the delivery into host cells of specific protein substrates critical to pathogenesis. Shigella spp. are Gram-negative bacterial pathogens responsible for human bacillary dysentery. The effector function of several Shigella T3SA substrates has largely been studied but their potential cellular targets are far from having been comprehensively delineated. In addition, it is likely that some T3SA substrates have escaped scrutiny as yet. Indeed, sequencing of the virulence plasmid of Shigella flexneri has revealed numerous open reading frames with unknown functions that could encode additional T3SA substrates. Taking advantage of label-free mass spectrometry detection of proteins secreted by a constitutively secreting strain of S. flexneri, we identified five novel substrates of the T3SA. We further confirmed their secretion through the T3SA and translocation into host cells using b-lactamase assays. The coding sequences of two of these novel T3SA substrates (Orf13 and Orf131a) have a guanine-cytosine content comparable to those of T3SA components and effectors. The three other T3SA substrates identified (Orf48, Orf86 and Orf176) have significant homology with antitoxin moieties of type II Toxin-Antitoxin systems usually implicated in the maintenance of low copy plasmids. While Orf13 and Orf131a might constitute new virulence effectors contributing to S. flexneri pathogenicity, potential roles for the translocation into host cells of antitoxins or antitoxin-like proteins during Shigella infection are discussed.

2017-10-17 | PXD006086 | Pride

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Project description:Intracellular trafficking pathways in eukaryotic cells are essential to maintain organelle identity and structure, and to regulate cell communication with its environment. Shigella flexneri invades and subverts the human colonic epithelium by the injection of virulence factors through a type 3 secretion system (T3SS). In this work we report the multiple effects of two S. flexneri effectors, IpaJ and VirA, which target small GTPases of the Arf and Rab families, consequently inhibiting several intracellular trafficking pathways. IpaJ and VirA induce large-scale impairment of host protein secretion and block the recycling of surface receptors. Moreover, these two effectors decrease clathrin-dependent and -independent endocytosis. Therefore, S. flexneri infection induces a global blockage of host cell intracellular transport, affecting the exchange between cells and their external environment. The combined action of these effectors disorganizes the epithelial cell polarity, disturbs epithelial barrier integrity, promotes multiple invasion events and enhances the pathogen capacity to penetrate into the colonic tissue in vivo.

2019-06-04 | PXD012291 | Pride

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