Plasmacytoid dendritic cells promote host defense against acute pneumovirus infection via the TLR7-MyD88-dependent signaling pathway.
Plasmacytoid dendritic cells promote host defense against acute pneumovirus infection via the TLR7-MyD88-dependent signaling pathway.
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DOI：
10.4049/jimmunol.1002635
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发表时间：
2011-05-15
期刊：
影响因子：
--
通讯作者：
Phipps S
中科院分区：
文献类型：
--
作者：
Davidson S;Kaiko G;Loh Z;Lalwani A;Zhang V;Spann K;Foo SY;Hansbro N;Uematsu S;Akira S;Matthaei KI;Rosenberg HF;Foster PS;Phipps S
人类呼吸道合胞病毒（RSV）是婴儿下呼吸道感染的主要原因。在人类婴儿中，浆细胞样树突状细胞 (pDC) 在感染期间被募集到鼻腔室，并通过分泌 I 型 IFN、IL-12 和 IL-6 启动宿主防御。然而，RSV 感染的 pDC 对 TLR7 介导的激活具有抵抗力。在这里，我们使用啮齿动物特异性病原体小鼠肺炎病毒 (PVM) 来确定 pDC 和 TLR7 信号传导对先天炎症和早期适应性免疫反应发展的贡献。在野生型 (WT) 而非 TLR7 或骨髓分化蛋白 88 (MyD88) 缺陷的小鼠中，PVM 接种导致 pDC 显着浸润，并增加 I、II 和 III 型 IFN 的表达。在 TLR7 或 MyD88 缺失的情况下，IFN 的延迟诱导与先天炎症反应的减弱和肺组织中病毒回收的增强有关。在缺乏 TLR7 的情况下，PVM 特异性 CD8+ T 细胞细胞因子的产生被消除。将 TLR7 充足但不缺乏 TLR7 的 pDC 过继转移至 TLR7 基因缺失的小鼠体内，重现了在 WT 小鼠中观察到的抗病毒反应，并促进了病毒清除。总之，pDC 介导的 TLR7 信号传导是对急性肺病毒感染的适当先天反应所必需的。可以想象，TLR7 信号通路中尚未确定的缺陷可能与健康人类婴儿中 RSV 相关发病率和死亡率升高有关。
Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in infants. In human infants, plasmacytoid dendritic cells (pDC) are recruited to the nasal compartment during infection and initiate host defense through the secretion of type I IFN, IL-12 and IL-6. However, RSV-infected pDCs are refractory to TLR7-mediated activation. Here, we used the rodent-specific pathogen, pneumonia virus of mice (PVM), to determine the contribution of pDC and TLR7-signaling to the development of the innate inflammatory and early adaptive immune response. In wild-type (WT) but not TLR7- or myeloid differentiation protein 88 (MyD88)-deficient mice, PVM inoculation led to a marked infiltration of pDCs and increased expression of type I, II and III IFNs. The delayed induction of IFNs in the absence of TLR7 or MyD88 was associated with a diminished innate inflammatory response and augmented virus recovery from lung tissue. In the absence of TLR7, PVM-specific CD8+ T cell cytokine production was abrogated. The adoptive transfer of TLR7-sufficient but not TLR7-deficient pDC to TLR7-gene-deleted mice recapitulated the antiviral responses observed in WT mice and promoted virus clearance. In summary, TLR7-mediated signaling by pDC is required for appropriate innate responses to acute pneumovirus infection. It is conceivable that as-yet-unidentified defects in the TLR7 signaling pathway may be associated with elevated levels of RSV-associated morbidity and mortality among otherwise healthy human infants.
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