Synergistic interactions of TLR2/6 and TLR9 induce a high level of resistance to lung infection in mice.
Synergistic interactions of TLR2/6 and TLR9 induce a high level of resistance to lung infection in mice.
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DOI：
10.4049/jimmunol.1002122
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发表时间：
2011-05-15
期刊：
影响因子：
--
通讯作者：
Evans SE
中科院分区：
文献类型：
--
作者：
Duggan JM;You D;Cleaver JO;Larson DT;Garza RJ;Guzmán Pruneda FA;Tuvim MJ;Zhang J;Dickey BF;Evans SE
传染性肺炎在世界范围内造成不可接受的死亡负担。保护人群免受肺炎的努力历来集中在抗生素开发和疫苗增强的适应性免疫上。然而，我们最近报道，肺部的先天防御可以通过吸入细菌裂解物来治疗诱导，从而保护小鼠免受致命的肺炎。在这里，我们在小鼠中测试了Toll样受体（TLR）是这种抗菌现象所需的假设，并发现在没有TLR信号转导衔接蛋白MyD 88的情况下不能诱导耐药性。然后，我们试图通过用雾化的合成TLR配体刺激肺上皮来概括细菌裂解物所提供的保护。虽然大多数单一或组合处理不产生保护作用，但同时用TLR 2/6和TLR 9的配体处理赋予针对毒性革兰氏阳性和革兰氏阴性病原体的稳健的协同保护作用。保护作用与肺中快速的病原体杀灭有关，并且病原体杀灭可以从分离的肺上皮细胞诱导。综上所述，这些数据证明了在对肺炎的诱导抗性中对TLR的需求，揭示了TLR 2/6和TLR 9的显著的、出乎意料的协同相互作用，加强了支持肺上皮的抗微生物能力的新证据，并且可以为可以在高峰脆弱期期间保护患者免受肺炎的新型临床治疗提供基础。
Infectious pneumonias exact an unacceptable mortality burden worldwide. Efforts to protect populations from pneumonia have historically focused on antibiotic development and vaccine-enhanced adaptive immunity. However, we have recently reported that the lungs’ innate defenses can be therapeutically induced by inhalation of a bacterial lysate that protects mice against otherwise lethal pneumonia. Here, we tested in mice the hypothesis that Toll-like receptors (TLRs) are required for this antimicrobial phenomenon, and found that resistance could not be induced in the absence of the TLR signaling adaptor protein MyD88. We then attempted to recapitulate the protection afforded by the bacterial lysate by stimulating the lung epithelium with aerosolized synthetic TLR ligands. While most single or combination treatments yielded no protection, simultaneous treatment with ligands for TLR2/6 and TLR9 conferred robust, synergistic protection against virulent Gram-positive and Gram-negative pathogens. Protection was associated with rapid pathogen killing in the lungs, and pathogen killing could be induced from lung epithelial cells in isolation. Taken together, these data demonstrate the requirement for TLRs in inducible resistance against pneumonia, reveal a remarkable, unanticipated synergistic interaction of TLR2/6 and TLR9, reinforce the emerging evidence supporting the antimicrobial capacity of the lung epithelium, and may provide the basis for a novel clinical therapeutic that can protect patients against pneumonia during periods of peak vulnerability.
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影响因子：
64.8
作者：
Brandl, Katharina;Plitas, George;Mihu, Coralia N.;Ubeda, Carles;Jia, Ting;Fleisher, Martin;Schnabl, Bernd;DeMatteo, Ronald P.;Pamer, Eric G.
通讯作者：
Pamer, Eric G.
影响因子：
5.8
作者：
Clement CG;Tuvim MJ;Evans CM;Tuvin DM;Dickey BF;Evans SE
通讯作者：
Evans SE
肺上皮作为肺炎 - 病原体识别和信号转导的分子机制中的哨兵和效应系统。
影响因子：
5.8
作者：
Hippenstiel, Stefan;Opitz, Bastian;Schmeck, Bernd;Suttorp, Norbert
通讯作者：
Suttorp, Norbert
影响因子：
56.9
作者：
Aliprantis, AO;Yang, RB;Zychlinsky, A
通讯作者：
Zychlinsky, A
影响因子：
3.1
作者：
Cluff, CW;Baldridge, JR;Persing, DH
通讯作者：
Persing, DH