Natural killer cell-intrinsic type I IFN signaling controls Klebsiella pneumoniae growth during lung infection.
Natural killer cell-intrinsic type I IFN signaling controls Klebsiella pneumoniae growth during lung infection.
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自然杀伤细胞-内在I型IFN信号传导控制肺炎克雷伯菌在肺部感染期间的生长。
DOI：
10.1371/journal.ppat.1006696
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发表时间：
2017-11
期刊：
影响因子：
6.7
通讯作者：
Kovarik P
中科院分区：
文献类型：
--
作者：
Ivin M;Dumigan A;de Vasconcelos FN;Ebner F;Borroni M;Kavirayani A;Przybyszewska KN;Ingram RJ;Lienenklaus S;Kalinke U;Stoiber D;Bengoechea JA;Kovarik P
肺炎克雷伯氏菌是医院获得性肺炎的重要原因，并且由于最近分离出多药耐药菌株而成为令人担忧的病原体。了解协调K.宿主对肺炎杆菌的清除是极其重要的。在这里，我们表明，I型干扰素（IFN）信号保护免受肺部感染的K。通过启动肺泡巨噬细胞和自然杀伤（NK）细胞之间的细菌生长控制相互作用，I型干扰素是重要的，但不同的和不完全理解的调节防御细菌感染。I型IFN受体1（Ifnar 1）缺陷小鼠感染克雷伯氏菌。pneumoniae不能激活NK细胞衍生的IFN-γ产生。IFN-γ是杀菌作用和肺泡巨噬细胞产生NK细胞应答-扩增IL-12和CXCL 10所必需的。在Ifnar 1缺陷型宿主中，Ifnar 1-proficient NK细胞拯救了细菌清除和NK细胞IFN-γ。一致地，包括肺泡巨噬细胞、单核细胞和中性粒细胞在内的骨髓细胞中的I型IFN信号传导对于宿主防御和IFN-γ活化是不利的。Ifnar 1缺陷型宿主启动肺泡巨噬细胞和NK细胞之间的防御促进串扰的失败通过给予外源性IFN-γ来避免，所述外源性IFN-γ恢复内源性IFN-γ产生并限制细菌生长。这些数据确定NK细胞固有的I型IFN信号传导是K. pneumoniae的清除，并揭示了未来治疗开发的具体目标。多重耐药肺炎克雷伯菌菌株的分离显著缩小了治疗克雷伯菌感染的治疗选择，或者在某些情况下完全消除了治疗选择。针对免疫系统而不是病原体的治疗是重要的替代方案。尽管具有临床相关性，但我们对驱动该病原体清除的免疫反应的理解仍存在重大差距。I型干扰素（IFN）被认为是强大的免疫系统调节剂，但它们对细菌感染的影响是不同的，并且仍然难以捉摸。在这项研究中，我们表明，I型干扰素信号是必不可少的安装一个保护性和细菌清除促进免疫反应，对K。肺炎。K.肺炎诱导的I型IFN通过使NK细胞IFN-γ产生而在肺泡巨噬细胞和NK细胞之间引发串扰，这进而激活巨噬细胞抗微生物武器。I型IFN-应答性NK细胞或IFN-γ给药拯救K. I型IFN-无应答宿主中的肺炎链球菌清除率。我们的研究表明，操纵I型IFN或IFN-γ水平可能是治疗耐药克雷伯菌的有效策略。肺炎感染。
Klebsiella pneumoniae is a significant cause of nosocomial pneumonia and an alarming pathogen owing to the recent isolation of multidrug resistant strains. Understanding of immune responses orchestrating K. pneumoniae clearance by the host is of utmost importance. Here we show that type I interferon (IFN) signaling protects against lung infection with K. pneumoniae by launching bacterial growth-controlling interactions between alveolar macrophages and natural killer (NK) cells. Type I IFNs are important but disparate and incompletely understood regulators of defense against bacterial infections. Type I IFN receptor 1 (Ifnar1)-deficient mice infected with K. pneumoniae failed to activate NK cell-derived IFN-γ production. IFN-γ was required for bactericidal action and the production of the NK cell response-amplifying IL-12 and CXCL10 by alveolar macrophages. Bacterial clearance and NK cell IFN-γ were rescued in Ifnar1-deficient hosts by Ifnar1-proficient NK cells. Consistently, type I IFN signaling in myeloid cells including alveolar macrophages, monocytes and neutrophils was dispensable for host defense and IFN-γ activation. The failure of Ifnar1-deficient hosts to initiate a defense-promoting crosstalk between alveolar macrophages and NK cell was circumvented by administration of exogenous IFN-γ which restored endogenous IFN-γ production and restricted bacterial growth. These data identify NK cell-intrinsic type I IFN signaling as essential driver of K. pneumoniae clearance, and reveal specific targets for future therapeutic exploitations. The isolation of multidrug-resistant Klebsiella pneumoniae strains has significantly narrowed, or in some settings completely removed, the therapeutic options for the treatment of Klebsiella infections. Therapies targeting the immune system rather than the pathogen represent important alternatives. Despite the clinical relevance, there are still major gaps in our understanding of immune responses which drive the clearance of this pathogen. Type I interferons (IFNs) are known as powerful immune system regulators yet their effects on bacterial infections are disparate and remain elusive. In this study we show that type I IFN signaling is indispensable for mounting a protective and bacterial clearance-promoting immune response against K. pneumoniae. K. pneumoniae-induced type I IFNs launch a crosstalk between alveolar macrophages and NK cells by enabling NK cell IFN-γ production which in turn activates the macrophage anti-microbial armament. Type I IFN-responsive NK cells or IFN-γ administration rescue K. pneumoniae clearance in type I IFN-unresponsive hosts. Our study suggests that manipulation of type I IFN or IFN-γ levels might represent a valid strategy for treatment of drug-resistant K. pneumoniae infections.
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影响因子：
20.3
作者：
Kamphuis, Elisabeth;Junt, Tobias;Kalinke, Ulrich
通讯作者：
Kalinke, Ulrich
DOI：
10.1084/jem.20062648
发表时间：
2007-07-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
7.3
作者：
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通讯作者：
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