RIG-I overexpression decreases mortality of cigarette smoke exposed mice during influenza A virus infection.
RIG-I overexpression decreases mortality of cigarette smoke exposed mice during influenza A virus infection.
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DOI：
10.1186/s12931-017-0649-z
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发表时间：
2017-09-02
影响因子：
5.8
通讯作者：
Metcalf JP
中科院分区：
文献类型：
--
作者：
Wang X;Wu W;Zhang W;Leland Booth J;Duggan ES;Tian L;More S;Zhao YD;Sawh RN;Liu L;Zou MH;Metcalf JP
视黄酸诱导基因I（RIG-I）是病毒诱导的抗病毒干扰素（IFN）和促炎细胞因子的重要调节因子，参与清除病毒感染。香烟烟雾（CS）暴露会增加呼吸道感染的频率和严重程度。我们产生了RIG-I转基因（TG）小鼠品系，其在人肺特异性表面活性蛋白C启动子的控制下表达RIG-I基因产物。我们比较了用甲型流感病毒（IAV）攻击后RIG-I TG小鼠及其同窝匹配的野生型（WT）小鼠的死亡率和宿主免疫应答。RIG-I过表达增加了IAV感染小鼠的存活率。CS暴露增加感染IAV的WT小鼠的死亡率。值得注意的是，在CS暴露的动物中，RIG-I过表达对IAV感染期间存活率的影响增强。在支气管肺泡灌洗液中的蛋白质浓度、总细胞计数和炎性细胞组成方面，与假暴露的IAV感染的WT小鼠相比，CS暴露的IAV感染的WT小鼠在肺中具有抑制的先天性应答特征。在IAV感染期间，RIG-I过表达将CS暴露小鼠中的先天免疫应答恢复至假暴露WT小鼠中所见的应答，并且可能负责RIG-I TG小鼠中的存活率提高，因为恢复先于动物死亡。我们的研究结果表明，RIG-I在小鼠中的过表达是保护CS增强吸烟者对流感感染的易感性，和CS介导的RIG-I抑制可能是部分负责的发病率和死亡率增加的小鼠暴露于IAV。因此，优化RIG-I反应可能是CS增强的肺部感染的重要治疗策略，特别是由于IAV引起的感染。
Retinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines which participate in clearing viral infections. Cigarette smoke (CS) exposure increases the frequency and severity of respiratory tract infections. We generated a RIG-I transgenic (TG) mouse strain that expresses the RIG-I gene product under the control of the human lung specific surfactant protein C promoter. We compared the mortality and host immune responses of RIG-I TG mice and their litter-matched wild type (WT) mice following challenge with influenza A virus (IAV). RIG-I overexpression increased survival of IAV-infected mice. CS exposure increased mortality in WT mice infected with IAV. Remarkably, the effect of RIG-I overexpression on survival during IAV infection was enhanced in CS-exposed animals. CS-exposed IAV-infected WT mice had a suppressed innate response profile in the lung compared to sham-exposed IAV-infected WT mice in terms of the protein concentration, total cell count and inflammatory cell composition in the bronchoalveolar lavage fluid. RIG-I overexpression restored the innate immune response in CS-exposed mice to that seen in sham-exposed WT mice during IAV infection, and is likely responsible for enhanced survival in RIG-I TG mice as restoration preceded death of the animals. Our results demonstrate that RIG-I overexpression in mice is protective for CS enhanced susceptibility of smokers to influenza infection, and that CS mediated RIG-I suppression may be partially responsible for the increased morbidity and mortality of the mice exposed to IAV. Thus, optimizing the RIG-I response may be an important treatment strategy for CS-enhanced lung infections, particularly those due to IAV.
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作者：
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