IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid.
IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid.
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DOI：
10.1371/journal.ppat.1005408
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发表时间：
2016-02
期刊：
影响因子：
6.7
通讯作者：
Opitz B
中科院分区：
文献类型：
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作者：
Naujoks J;Tabeling C;Dill BD;Hoffmann C;Brown AS;Kunze M;Kempa S;Peter A;Mollenkopf HJ;Dorhoi A;Kershaw O;Gruber AD;Sander LE;Witzenrath M;Herold S;Nerlich A;Hocke AC;van Driel I;Suttorp N;Bedoui S;Hilbi H;Trost M;Opitz B
巨噬细胞可以是细菌病原体或抗菌效应细胞的小生境，这取决于病原体和来自免疫系统的信号。在这里，我们表明，I型和II型干扰素是嗜肺军团菌感染期间基因表达的主要调节因子，以及限制肺炎期间细菌生长的肺泡巨噬细胞内在免疫反应的激活剂。定量质谱分析表明，这两种干扰素大大修改军团菌含空泡，和比较分析显示不同的子集的转录和空间干扰素调节蛋白。免疫应答基因（IRG）1在与含军团菌的空泡密切相关的线粒体中由IFN诱导，并介导衣康酸的产生。这种代谢产物对液泡内L.嗜肺菌以及细胞外多重耐药革兰氏阳性和阴性细菌。我们的研究探讨了IFN在诱导细菌空泡的实质性重塑和刺激IRG1衍生的靶向空泡内病原体的衣康酸产生中的总体作用。IRG1或其产物衣康酸可能是治疗靶点，以对抗细胞内和耐药细菌。许多细胞内细菌病原体在巨噬细胞内的专门空泡中复制。本文系统研究了巨噬细胞内源性抗菌防御的分子机制及其影响。利用L. pneumophila是肺炎的重要原因和细胞内细菌的模式生物，我们发现I型和II型干扰素严重修饰细菌空泡的蛋白质组以限制感染。我们鉴定了IRG1，并证明了其代谢产物衣康酸对液泡中细菌的杀菌活性。此外，我们的研究为肺泡巨噬细胞中这种细胞自主防御途径限制肺部感染的影响提供了证据。我们推测，空泡IRG1或其产物衣康酸可以作为未来的治疗目标，以打击细胞内和耐药细菌。
Macrophages can be niches for bacterial pathogens or antibacterial effector cells depending on the pathogen and signals from the immune system. Here we show that type I and II IFNs are master regulators of gene expression during Legionella pneumophila infection, and activators of an alveolar macrophage-intrinsic immune response that restricts bacterial growth during pneumonia. Quantitative mass spectrometry revealed that both IFNs substantially modify Legionella-containing vacuoles, and comparative analyses reveal distinct subsets of transcriptionally and spatially IFN-regulated proteins. Immune-responsive gene (IRG)1 is induced by IFNs in mitochondria that closely associate with Legionella-containing vacuoles, and mediates production of itaconic acid. This metabolite is bactericidal against intravacuolar L. pneumophila as well as extracellular multidrug-resistant Gram-positive and -negative bacteria. Our study explores the overall role IFNs play in inducing substantial remodeling of bacterial vacuoles and in stimulating production of IRG1-derived itaconic acid which targets intravacuolar pathogens. IRG1 or its product itaconic acid might be therapeutically targetable to fight intracellular and drug-resistant bacteria. Numerous intracellular bacterial pathogens replicate in specialized vacuoles within macrophages. We systematically study the molecular mechanism and the impact of macrophage-intrinsic antibacterial defense. Using L. pneumophila, an important cause of pneumonia and model organism for intracellular bacteria, we found that type I and II interferons critically modify the proteome of bacterial vacuoles to restrict infection. We identify IRG1 and demonstrate a bactericidal activity of its metabolite itaconic acid on bacteria in their vacuole. Moreover, our study provides evidence for the impact of this cell-autonomous defense pathway in alveolar macrophages to restrict lung infection. We speculate that vacuolar IRG1 or its product itaconic acid could serve as future therapeutic targets to fight intracellular and drug-resistant bacteria.