Foronjy Robert F, Dabo Abdoulaye J, Cummins Neville, Geraghty Patrick
BMC Immunol. 2014 Oct 3;15:41. doi: 10.1186/s12865-014-0041-4.
Respiratory syncytial virus (RSV) infects the lung epithelium where it stimulates the production of numerous host cytokines that are associated with disease burden and acute lung injury. Characterizing the host cytokine response to RSV infection, the regulation of host cytokines and the impact of neutralizing an RSV-inducible cytokine during infection were undertaken in this study.
A549, primary human small airway epithelial (SAE) cells and wild-type, TIR-domain-containing adapter-inducing interferon-β (Trif) and mitochondrial antiviral-signaling protein (Mavs) knockout (KO) mice were infected with RSV and cytokine responses were investigated by ELISA, multiplex analysis and qPCR. Neutralizing anti-leukemia inhibitory factor (LIF) IgG or control IgG was administered to a group of wild-type animals prior to RSV infection.
RSV-infected A549 and SAE cells release a network of cytokines, including newly identified RSV-inducible cytokines LIF, migration inhibitory factor (MIF), stem cell factor (SCF), CCL27, CXCL12 and stem cell growth factor beta (SCGF-β). These RSV-inducible cytokines were also observed in the airways of mice during an infection. To identify the regulation of RSV inducible cytokines, Mavs and Trif deficient animals were infected with RSV. In vivo induction of airway IL-1β, IL-4, IL-5, IL-6, IL-12(p40), IFN-γ, CCL2, CCL5, CCL3, CXCL1, IP-10/CXCL10, IL-22, MIG/CXCL9 and MIF were dependent on Mavs expression in mice. Loss of Trif expression in mice altered the RSV induction of IL-1β, IL-5, CXCL12, MIF, LIF, CXCL12 and IFN-γ. Silencing of retinoic acid-inducible gene-1 (RIG-I) expression in A549 cells had a greater impact on RSV-inducible cytokines than melanoma differentiation-associated protein 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2), and Trif expression. To evaluate the role of LIF in the airways during RSV infection, animals were treated with neutralizing anti-LIF IgG, which enhanced RSV pathology observed with increased airspace protein content, apoptosis and airway hyperresponsiveness compared to control IgG treatment.
RSV infection in the epithelium induces a network of immune factors to counter infection, primarily in a RIG-I dependent manner. Expression of LIF protects the lung from lung injury and enhanced pathology during RSV infection.
呼吸道合胞病毒（RSV）感染肺上皮细胞，刺激产生众多与疾病负担和急性肺损伤相关的宿主细胞因子。本研究对宿主细胞因子对RSV感染的反应、宿主细胞因子的调控以及感染期间中和一种RSV诱导的细胞因子的影响进行了表征。
用RSV感染A549细胞、原代人小气道上皮（SAE）细胞以及野生型、含TIR结构域的接头诱导干扰素-β（Trif）和线粒体抗病毒信号蛋白（Mavs）基因敲除（KO）小鼠，并通过酶联免疫吸附测定（ELISA）、多重分析和定量聚合酶链反应（qPCR）研究细胞因子反应。在RSV感染前，对一组野生型动物给予中和抗白血病抑制因子（LIF）IgG或对照IgG。
RSV感染的A549细胞和SAE细胞释放出一个细胞因子网络，包括新发现的RSV诱导细胞因子LIF、迁移抑制因子（MIF）、干细胞因子（SCF）、CCL27、CXCL12和干细胞生长因子β（SCGF-β）。在感染期间，在小鼠气道中也观察到了这些RSV诱导细胞因子。为了确定RSV诱导细胞因子的调控机制，则用RSV感染Mavs和Trif缺陷动物。小鼠气道中白细胞介素-1β（IL-1β）、IL-4、IL-5、IL-6、IL-12（p40）、干扰素-γ（IFN-γ）、CCL2、CCL5、CCL3、CXCL1、IP-10/CXCL10、IL-22、MIG/CXCL9和MIF的体内诱导依赖于Mavs的表达。小鼠Trif表达缺失改变了RSV对IL-1β、IL-5、CXCL12、MIF、LIF、CXCL12和IFN-γ 的诱导作用。在A549细胞中，视黄酸诱导基因-1（RIG-I）表达的沉默对RSV诱导细胞因子的影响大于黑色素瘤分化相关蛋白5（MDA5）和遗传与生理学实验室2（LGP2）以及Trif表达。为了评估LIF在RSV感染期间气道中的作用，用中和抗LIF IgG处理动物，与对照IgG处理相比，这增强了观察到的RSV病理变化，表现为气腔蛋白含量增加、细胞凋亡和气道高反应性。
上皮细胞中的RSV感染诱导了一个免疫因子网络来对抗感染，主要是以RIG-I依赖的方式。LIF的表达可保护肺免受RSV感染期间的肺损伤和增强的病理变化。
