Section of Pulmonary, Critical Care, & Sleep Medicine, Yale University, New Haven, Connecticut, USA.
Division of Pulmonary, Critical Care, Allergy & Sleep Medicine, University of California San Francisco, San Francisco, California, USA.
Mucosal Immunol. 2018 May;11(3):958-967. doi: 10.1038/mi.2017.120. Epub 2018 Feb 7.
Respiratory syncytial virus (RSV) persists as a significant human pathogen that continues to contribute to morbidity and mortality. In children, RSV is the leading cause of lower respiratory tract infections, and in adults RSV causes pneumonia and contributes to exacerbations of chronic lung diseases. RSV induces airway epithelial inflammation by activation of the epidermal growth factor receptor (EGFR), a tyrosine kinase receptor. Recently, EGFR inhibition was shown to decrease RSV infection, but the mechanism(s) for this effect are not known. Interferon (IFN) signaling is critical for innate antiviral responses, and recent experiments have implicated IFN-λ (lambda), a type III IFN, as the most significant IFN for mucosal antiviral immune responses to RSV infection. However, a role for RSV-induced EGFR activation to suppress airway epithelial antiviral immunity has not been explored. Here, we show that RSV-induced EGFR activation suppresses IFN regulatory factor (IRF) 1-induced IFN-λ production and increased viral infection, and we implicate RSV F protein to mediate this effect. EGFR inhibition, during viral infection, augmented IRF1, IFN-λ, and decreased RSV titers. These results suggest a mechanism for EGFR inhibition to suppress RSV by activation of endogenous epithelial antiviral defenses, which may be a potential target for novel therapeutics.
呼吸道合胞病毒（RSV）仍然是一种重要的人类病原体，持续导致发病率和死亡率。在儿童中，RSV 是下呼吸道感染的主要原因，在成人中，RSV 会导致肺炎，并导致慢性肺部疾病恶化。RSV 通过激活表皮生长因子受体（EGFR），一种酪氨酸激酶受体，引起气道上皮炎症。最近，EGFR 抑制被证明可以减少 RSV 感染，但这种作用的机制尚不清楚。干扰素（IFN）信号对于先天抗病毒反应至关重要，最近的实验表明，IFN-λ（lambda），一种 III 型 IFN，是针对 RSV 感染的粘膜抗病毒免疫反应最重要的 IFN。然而，RSV 诱导的 EGFR 激活抑制气道上皮抗病毒免疫的作用尚未得到探索。在这里，我们表明 RSV 诱导的 EGFR 激活抑制 IFN 调节因子（IRF）1 诱导的 IFN-λ 产生和增加的病毒感染，我们暗示 RSV F 蛋白介导这种作用。在病毒感染期间，EGFR 抑制增强了 IRF1、IFN-λ，并降低了 RSV 滴度。这些结果表明，EGFR 抑制通过激活内源性上皮抗病毒防御来抑制 RSV 的机制，这可能是新型治疗药物的潜在靶点。
