Browsing by Author "Hardisty, Gareth R."

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    CAGE sequencing reveals CFTR-dependent dysregulation of type I IFN signaling in activated cystic fibrosis macrophages
    (AAAS, 2023) Gillan, Jonathan L.; Chokshi, Mithil; Hardisty, Gareth R.; Clohisey Hendry, Sara; Prasca-Chamorro, Daniel; Robinson, Nicola J.; Lasota, Benjamin; Clark, Richard; Murphy, Lee; Whyte, Moira K. B.; Baillie, J. Kenneth; Davidson, Donald J.; Bao, Gang; Gray, Robert D.
    An intense, nonresolving airway inflammatory response leads to destructive lung disease in cystic fibrosis (CF). Dysregulation of macrophage immune function may be a key facet governing the progression of CF lung disease, but the underlying mechanisms are not fully understood. We used 5′ end centered transcriptome sequencing to profile P. aeruginosa LPS-activated human CF macrophages, showing that CF and non-CF macrophages deploy substantially distinct transcriptional programs at baseline and following activation. This includes a significantly blunted type I IFN signaling response in activated patient cells relative to healthy controls that was reversible upon in vitro treatment with CFTR modulators in patient cells and by CRISPR-Cas9 gene editing to correct the F508del mutation in patient-derived iPSC macrophages. These findings illustrate a previously unidentified immune defect in human CF macrophages that is CFTR dependent and reversible with CFTR modulators, thus providing new avenues in the search for effective anti-inflammatory interventions in CF.