Dataset Information

Controlling Epithelial Polarity: A Human Enteroid Model for Host-Pathogen Interactions.

ABSTRACT: Human enteroids-epithelial spheroids derived from primary gastrointestinal tissue-are a promising model to study pathogen-epithelial interactions. However, accessing the apical enteroid surface is challenging because it is enclosed within the spheroid. We developed a technique to reverse enteroid polarity such that the apical surface everts to face the media. Apical-out enteroids maintain proper polarity and barrier function, differentiate into the major intestinal epithelial cell (IEC) types, and exhibit polarized absorption of nutrients. We used this model to study host-pathogen interactions and identified distinct polarity-specific patterns of infection by invasive enteropathogens. Salmonella enterica serovar Typhimurium targets IEC apical surfaces for invasion via cytoskeletal rearrangements, and Listeria monocytogenes, which binds to basolateral receptors, invade apical surfaces at sites of cell extrusion. Despite different modes of entry, both pathogens exit the epithelium within apically extruding enteroid cells. This model will enable further examination of IECs in health and disease.

SUBMITTER: Co JY

PROVIDER: S-EPMC6391775 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Controlling Epithelial Polarity: A Human Enteroid Model for Host-Pathogen Interactions.

Co Julia Y JY Margalef-Català Mar M Li Xingnan X Mah Amanda T AT Kuo Calvin J CJ Monack Denise M DM Amieva Manuel R MR

Cell reports 20190201 9

Human enteroids-epithelial spheroids derived from primary gastrointestinal tissue-are a promising model to study pathogen-epithelial interactions. However, accessing the apical enteroid surface is challenging because it is enclosed within the spheroid. We developed a technique to reverse enteroid polarity such that the apical surface everts to face the media. Apical-out enteroids maintain proper polarity and barrier function, differentiate into the major intestinal epithelial cell (IEC) types, a ...[more]

PMID: 30811997

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Project description:The goal of this project is to understand the etiology and pathology of host-pathogen interaction using high-throughput cellular phenotyping. By combining the expertise in pathogen biology, informatics and stem cell biology across the institute, this project will use targeted genetic modification in mouse embryonic stem cells to identify functions of host genes in innate immunity. We will also explore the biology of mouse embryonic stem cells and their differentiation into immune competent cells. To this end we will generate homozygous and inducible knockout lines in mouse embryonic stem cells, which will be differentiated into immune competent cells, such as macrophages or dendritic cells. These will be subjected to a panel of immune challenge and stimulation assays to characterise the functions of the disrupted genes. To identify new functions for mammalian genes in innate immunity we will:\Generate a panel of homozygous inducible gene knockout mouse ES cell lines working from a list of ca. 80 candidate genes (MGP phenotyping and GWAS hits). \Scale up differentiation protocols for immune challenge and stimulation assays.\Benchmark in vitro differentiated ES cell models against primary immune cells from selected MGP mouse lines and eventually against human iPS cells.\Screen a panel of 30 genetically modified cell lines in immunological challenge and stimulation assays, defining phenotypes at the cellular level by high content imaging, biochemically by assaying cytokine production, and at the molecular level by transcriptome analysis.\Define novel gene functions in innate immunity through network analysis of gene expression data from all challenged cell lines.\In the longer term scale up the production and phenotyping of genetically modified cell lines (mouse or human as appropriate).This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

Dataset Information

Controlling Epithelial Polarity: A Human Enteroid Model for Host-Pathogen Interactions.

Publications

Controlling Epithelial Polarity: A Human Enteroid Model for Host-Pathogen Interactions.

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