BACKGROUND Aberrant responses by the cystic fibrosis airway epithelium during viral infection may underly the clinical observations. Whether CFTR modulators affect antiviral responses by CF epithelia is presently unknown. We tested the hypothesis that treatment of CF epithelial cells with ivacaftor (Iva) or ivacaftor/lumacaftor (Iva/Lum) would improve control of rhinovirus infection. METHODS Nineteen CF epithelial cultures (10 homozygous for p.Phe508del as CFTR Class 2, 9 p.Phe508del/p.Gly551Asp as Class 3) were infected with rhinovirus 1B at multiplicity of infection 12 for 24 h. Culture RNA and supernatants were harvested to assess gene and protein expression respectively. RESULTS RNA-seq analysis comparing rhinovirus infected cultures to control identified 796 and 629 differentially expressed genes for Class 2 and Class 3, respectively. This gene response was highly conserved when cells were treated with CFTR modulators and were predicted to be driven by the same interferon-pathway transcriptional regulators (IFNA, IFNL1, IFNG, IRF7, STAT1). Direct comparisons between treated and untreated infected cultures did not yield any differentially expressed genes for Class 3 and only 68 genes for Class 2. Changes were predominantly related to regulators of lipid metabolism and inflammation, aspects of epithelial biology known to be dysregulated in CF. In addition, CFTR modulators did not affect viral copy number, or levels of pro-inflammatory cytokines produced post-infection. CONCLUSIONS Though long-term clinical data is not yet available, results presented here suggest that first generation CFTR modulators do not interfere with core airway epithelial responses to rhinovirus infection. Future work should investigate the latest triple modulation therapies.

中文翻译：

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Ivacaftor 或 lumacaftor/ivacaftor 治疗不会改变核心 CF 气道上皮基因对鼻病毒的反应

背景病毒感染期间囊性纤维化气道上皮的异常反应可能是临床观察的基础。目前尚不清楚 CFTR 调节剂是否会影响 CF 上皮细胞的抗病毒反应。我们测试了以下假设：用 ivacaftor (Iva) 或 ivacaftor/lumacaftor (Iva/Lum) 处理 CF 上皮细胞将改善对鼻病毒感染的控制。方法 19 个 CF 上皮培养物（10 个纯合的 p.Phe508del 为 CFTR 2 类，9 个 p.Phe508del/p.Gly551Asp 为 3 类）用鼻病毒 1B 以感染复数 12 感染 24 小时。收获培养物 RNA 和上清液以分别评估基因和蛋白质的表达。结果 比较鼻病毒感染的培养物与对照的 RNA-seq 分析分别确定了 2 类和 3 类的 796 和 629 个差异表达基因。当细胞用 CFTR 调节剂处理时，这种基因反应是高度保守的，并且预计由相同的干扰素途径转录调节剂（IFNA、IFNL1、IFNG、IRF7、STAT1）驱动。处理和未处理的感染培养物之间的直接比较没有产生任何差异表达的第 3 类基因，只有 68 个基因用于第 2 类。变化主要与脂质代谢和炎症的调节剂有关，已知在 CF 中上皮生物学的某些方面失调。此外，CFTR 调节剂不影响病毒拷贝数或感染后产生的促炎细胞因子的水平。结论 虽然长期临床数据尚不可用，但此处显示的结果表明第一代 CFTR 调节剂不会干扰对鼻病毒感染的核心气道上皮反应。