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

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. Microarray experiments were performed as dual-color hybridizations on Agilent-026652 human whole genome catalog 44K arrays. To compensate for dye-specific effects, a dye-reversal independent color-swap with two biological replicates was applied. Microarray image data were analyzed and processed with the Image Analysis/Feature Extraction software G2567AA v. A.11.5.1.1 (Agilent Technologies) using default settings and the GE2_1105_Oct12 extraction protocol.