Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia.
Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia.
复制标题
Toll样受体（TLR）3对病毒诱导的急性肺炎的有害贡献。
DOI：
10.1371/journal.ppat.0020053
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发表时间：
2006-06
期刊：
影响因子：
6.7
通讯作者：
Si-Tahar, Mustapha
中科院分区：
文献类型：
--
作者：
Le Goffic, Ronan;Balloy, Viviane;Lagranderie, Micheline;Alexopoulou, Lena;Escriou, Nicolas;Flavell, Richard;Chignard, Michel;Si-Tahar, Mustapha
甲型流感病毒（IAV）是一种高度传染性的急性呼吸道疾病的病原体，每年引起流行病和相当大的死亡率。最近，我们使用体外方法证明，模式识别Toll样受体（TLR）3在肺上皮细胞对IAV的免疫应答中起着关键作用。鉴于这些数据和TLR 3在体内的功能作用仍有争议的事实，我们设计了一项调查，以更好地了解TLR 3在IAV发病机制和宿主免疫应答中的作用，使用实验小鼠模型。在感染的野生型和TLR 3 −/−小鼠中比较了几个动态参数的时间过程，包括动物存活率、呼吸道痛苦、病毒清除、白细胞募集到空气中以及关键炎症介质的分泌。首先，我们发现TLR 3的肺部表达是组成性的，并且在对照小鼠中流感感染后显著上调。值得注意的是，与野生型小鼠相比，感染TLR 3 −/−的动物显示出显著减少的炎症介质，包括RANTES（活化后调节，正常T细胞表达和分泌），白细胞介素-6和白细胞介素-12 p40/p70，以及支气管肺泡空气中较低数量的CD 8 + T淋巴细胞。更重要的是，尽管肺部的病毒产量较高，但缺乏TLR 3的小鼠具有意想不到的生存优势。因此，据我们所知，我们的研究结果首次表明，TLR 3-IAV相互作用对有害的宿主炎症反应的衰弱作用起着关键作用。甲型流感病毒（IAV）是高度传染性的急性呼吸道疾病。最近，人们越来越担心在不久的将来可能发生流感大流行。因此，需要更好地了解IAV发病机制和宿主免疫应答的分子机制，以开发更有效的预防和治疗流感的手段。Toll样受体（TLR）3是检测微生物并触发宿主防御的受体家族的成员。我们先前使用体外方法证明，TLR 3在肺上皮细胞对IAV的应答中起关键作用。在这里，我们使用小鼠模型来剖析流感期间TLR 3依赖性应答的体内重要性。在感染的对照野生型和TLR 3缺陷小鼠中比较了几个参数的时间过程，包括动物存活率、呼吸窘迫、病毒清除和炎症。我们的研究结果表明，TLR 3 −/−小鼠对IAV攻击具有意想不到的优势，因为我们首次表明TLR 3介导的炎症反应的减少减少了IAV诱导的肺炎的临床表现。
Influenza A virus (IAV) is the etiological agent of a highly contagious acute respiratory disease that causes epidemics and considerable mortality annually. Recently, we demonstrated, using an in vitro approach, that the pattern recognition Toll-like receptor (TLR)3 plays a key role in the immune response of lung epithelial cells to IAV. In view of these data and the fact that the functional role of TLR3 in vivo is still debated, we designed an investigation to better understand the role of TLR3 in the mechanisms of IAV pathogenesis and host immune response using an experimental murine model. The time-course of several dynamic parameters, including animal survival, respiratory suffering, viral clearance, leukocyte recruitment into the airspaces and secretion of critical inflammatory mediators, was compared in infected wild-type and TLR3 −/− mice. First, we found that the pulmonary expression of TLR3 is constitutive and markedly upregulated following influenza infection in control mice. Notably, when compared to wild-type mice, infected TLR3 −/− animals displayed significantly reduced inflammatory mediators, including RANTES (regulated upon activation, normal T cell expressed and secreted), interleukin-6, and interleukin-12p40/p70 as well as a lower number of CD8+ T lymphocytes in the bronchoalveolar airspace. More important, despite a higher viral production in the lungs, mice deficient in TLR3 had an unexpected survival advantage. Hence, to our knowledge, our findings show for the first time that TLR3-IAV interaction critically contributes to the debilitating effects of a detrimental host inflammatory response. Influenza A virus (IAV) is responsible for highly contagious acute respiratory disease. Recent concerns have risen concerning a possible influenza pandemic in the near future. Thus, a better understanding of the molecular mechanisms of IAV pathogenesis and host immune responses is required for the development of more efficient means of prevention and treatment of influenza. The Toll-like receptor (TLR)3 is a member of a family of receptors that detects microbes and triggers host defenses. We previously demonstrated using an in vitro approach, that the TLR3 plays a key role in the response of lung epithelial cells to IAV. Here, we used a mouse model to dissect the in vivo importance of TLR3-dependent responses during influenza. The time-course of several parameters, including animal survival, respiratory distress, viral clearance, and inflammation, was compared in infected control wild-type and TLR3-deficient mice. Our findings reveal that TLR3 −/− mice have an unexpected advantage against IAV challenge as we show for the first time that a reduction of TLR3-mediated inflammatory response reduces the clinical manifestations of IAV-induced pneumonia.