Reduced Expression of IRF7 in Nasal Epithelial Cells from Smokers after Infection with Influenza
Reduced Expression of IRF7 in Nasal Epithelial Cells from Smokers after Infection with Influenza
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DOI：
10.1165/rcmb.2009-0254oc
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发表时间：
2010-09-01
影响因子：
6.4
通讯作者：
Noah, Terry L.
中科院分区：
文献类型：
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作者：
Jaspers, Ilona;Horvath, Katherine M.;Noah, Terry L.
吸烟者更容易受到呼吸道病毒感染，包括流感病毒，但介导这种影响的机制尚不清楚。为了确定上皮细胞如何促进吸烟者中观察到的增强的易感性，我们建立了来自吸烟者的分化的鼻上皮细胞（NEC）的体外模型，其显示增强的粘蛋白表达。吸烟者的NECs对流感病毒感染的反应比非吸烟者的NECs具有更大的细胞毒性，白细胞介素-6的释放和病毒脱落。关注I型干扰素（IFN）的表达，我们观察到吸烟者感染流感的NECs产生的IFN-α显著低于非吸烟者的NECs。同样，IRF 7的表达，一个控制IFN-α表达的关键转录因子，在流感感染和IFN-β刺激的吸烟者的NEC中显著降低。此外，我们的数据表明，IRF 7基因的DNA甲基化和DNA（胞嘧啶-5-）-甲基转移酶1的表达在吸烟者的NEC中增强。为了在体内证实这些发现，我们启动了一项研究，其中吸烟和不吸烟的健康志愿者鼻内接种减毒活流感病毒（LAIV）疫苗，并在LAIV给药前后进行鼻活检。LAIV诱导的IRF 7表达在吸烟者的鼻上皮中较低，支持我们的体外观察结果。这些数据表明，流感感染导致吸烟者的NEC中转录因子IRF 7的表达减少，并且这些效应可能由IRF 7基因的表观遗传修饰介导，从而提供了使吸烟者更容易受到呼吸道病毒感染的潜在机制。
Smokers are more susceptible to respiratory viral infections, including influenza virus, but the mechanisms mediating this effect are unknown. To determine how epithelial cells contribute to the enhanced susceptibility seen in smokers, we established an in vitro model of differentiated nasal epithelial cells (NECs) from smokers, which showed enhanced mucin expression. The NECs from smokers responded to influenza infection with greater cytotoxicity, release of interleukin-6, and viral shedding than NECs from nonsmokers. Focusing on type I interferon (IFN) expression, we observed that influenza-infected NECs from smokers produced significantly less IFN-alpha than NECs from nonsmokers. Similarly, the expression of IRF7, a key transcription factor controlling the expression of IFN-alpha, was significantly decreased in influenza-infected and IFN-beta-stimulated NECs from smokers. Furthermore, our data indicate that the DNA methylation of the IRF7 gene and expression of the DNA (cytosine-5-)- methyltransferase 1 was enhanced in NECs from smokers. To confirm these findings in vivo, we initiated a study in which smoking and nonsmoking healthy volunteers were inoculated nasally with the live-attenuated influenza virus (LAIV) vaccine, and nasal biopsies were obtained before and after the administration of LAIV. The LAIV-induced expression of IRF7 was lower in the nasal epithelium from smokers, supporting our in vitro observations. These data demonstrate that infection with influenza results in the reduced expression of transcription factor IRF7 in NECs from smokers, and that these effects may be mediated by an epigenetic modification of the IRF7 gene, thus providing a potential mechanism rendering smokers more susceptible to respiratory virus infections.