Streptococcus pneumoniae DNA initiates type I interferon signaling in the respiratory tract.
Streptococcus pneumoniae DNA initiates type I interferon signaling in the respiratory tract.
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作者：
Parker D;Martin FJ;Soong G;Harfenist BS;Aguilar JL;Ratner AJ;Fitzgerald KA;Schindler C;Prince A
粘膜上皮是所有类型的呼吸道病原体的初始靶点。虽然I型干扰素（IFN）信号转导传统上与抗病毒免疫相关，但我们证明了细胞外细菌病原体肺炎链球菌激活气道上皮细胞和树突状细胞中的I型IFN级联反应。这种反应依赖于成孔毒素肺炎球菌溶血素。肺炎球菌DNA通过DAI/STING/TBK 1/IRF 3级联激活IFN-β表达。Tlr 4-/-、Myd 88-/-、Trif-/-和Nod 2-/-突变小鼠对I型IFN信号传导没有损害。I型IFN信号传导的诱导有助于根除肺炎球菌携带，因为与野生型小鼠相比，IFN-α/β受体敲除小鼠具有显著增加的肺炎链球菌鼻定殖。这些研究表明，I型IFN级联是气道细菌病原体的粘膜反应的中心组成部分，并响应于能够进入细胞内受体的细菌病原体相关分子模式。肺炎链球菌（Streptococcus pneumoniae）是细菌性肺炎的主要原因，每年在全球范围内导致超过一百万人死亡，并造成重大的经济负担。尽管已知抗体对于有效的吞噬作用是关键的，但尚不知道粘膜上皮如何感知该病原体。我们证明，这种细胞外病原体激活粘膜信号通常由病毒病原体通过肺炎球菌溶血素孔激活细胞内受体和I型干扰素（IFN）级联激活。缺乏I型IFN受体的小鼠清除肺炎链球菌的能力降低，表明I型IFN级联是粘膜清除这种重要病原体的核心。
The mucosal epithelium is the initial target for respiratory pathogens of all types. While type I interferon (IFN) signaling is traditionally associated with antiviral immunity, we demonstrate that the extracellular bacterial pathogen Streptococcus pneumoniae activates the type I IFN cascade in airway epithelial and dendritic cells. This response is dependent upon the pore-forming toxin pneumolysin. Pneumococcal DNA activates IFN-β expression through a DAI/STING/TBK1/IRF3 cascade. Tlr4−/−, Myd88−/−, Trif−/−, and Nod2−/− mutant mice had no impairment of type I IFN signaling. Induction of type I IFN signaling contributes to the eradication of pneumococcal carriage, as IFN-α/β receptor null mice had significantly increased nasal colonization with S. pneumoniae compared with that of wild-type mice. These studies suggest that the type I IFN cascade is a central component of the mucosal response to airway bacterial pathogens and is responsive to bacterial pathogen-associated molecular patterns that are capable of accessing intracellular receptors. The bacterium Streptococcus pneumoniae is a leading cause of bacterial pneumonia, leading to upwards of one million deaths a year worldwide and significant economic burden. Although it is known that antibody is critical for efficient phagocytosis, it is not known how this pathogen is sensed by the mucosal epithelium. We demonstrate that this extracellular pathogen activates mucosal signaling typically activated by viral pathogens via the pneumolysin pore to activate intracellular receptors and the type I interferon (IFN) cascade. Mice lacking the receptor to type I IFNs have a reduced ability to clear S. pneumoniae, suggesting that the type I IFN cascade is central to the mucosal clearance of this important pathogen.