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Interfering with interferons: cholesterol modification by Helicobacter pylori prevents IFN receptor assembly

ABSTRACT: Interferons (IFNs) are thought to primarily protect against intracellular pathogens. Here we show that Helicobacter pylori, a chronic colonizer of gastric mucosal surfaces, effectively blocks both type I and type II IFN signalling via cholesterol-α-glucosyltransferase (CaGT). Thus, CaGT, causing depletion of cholesterol from host cells, prevents infected epithelial cells from executing crucial effector functions, including the production of human b-defensin 3 (hBD3). Cholesterol depletion by CaGT prevents the assembly of interferon receptors resulting in a failure of JAK/STAT1 activation and subsequent expression of downstream transcriptional regulators (IRF-1 and 7), T-cell chemo-attractants (CXCL9 and 10) and antimicrobial peptides. Moreover, infection of human primary gastric epithelial cells by H. pylori also prevents residual type I IFN autocrine signalling and thereby further dampens the response to type II IFNs. Our results uncover a cooperative role for type I and type II IFNs in the defense against extracellular bacteria and explain the mechanism by which cholesterol modification by H. pylori usurps epithelial cell effector function, normally triggered by T-cell-derived inflammatory signals. Accordingly, CaGT acts as a central pathogenesis determinant and immune modulator of H. pylori contributing to this pathogen's exceptional ability of life-long persistence.

ORGANISM(S): Homo sapiens

PROVIDER: GSE76589 | GEO | 2018/03/02

REPOSITORIES: GEO

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