Lipid droplet formation in Mycobacterium tuberculosis infected macrophages requires IFN-γ/HIF-1α signaling and supports host defense.
Lipid droplet formation in Mycobacterium tuberculosis infected macrophages requires IFN-γ/HIF-1α signaling and supports host defense.
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DOI：
10.1371/journal.ppat.1006874
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发表时间：
2018-01
期刊：
影响因子：
6.7
通讯作者：
Stanley S
中科院分区：
文献类型：
--
作者：
Knight M;Braverman J;Asfaha K;Gronert K;Stanley S
脂滴（LD）的形成发生在巨噬细胞感染许多细胞内病原体，包括结核分枝杆菌。据信M.结核病和其它细菌特异性地引起LD形成作为致病策略，以便产生宿主脂质的贮库，用作碳源以促进细胞内生长。在这里，我们表明，LD的形成是不是一个细菌驱动的过程中M。结核病感染，而是作为作为宿主防御机制的一部分的巨噬细胞的免疫激活的结果而发生。我们发现，IFN-γ驱动的，HIF-1α依赖的信号通路，以前参与宿主防御，重新分配巨噬细胞脂质进入LD。此外，我们还证明了M.结核杆菌能够在不存在LD的情况下获得宿主脂质，但在存在IFN-γ诱导的LD的情况下不能。该结果将巨噬细胞LD形成与细菌获得宿主脂质解偶联。此外，我们表明IFN-γ驱动的LD形成支持宿主保护性类花生酸（包括PGE 2和LXB 4）的产生。最后，我们证明了HIF-1α及其靶基因Hig 2是感染M.结核病，从而证明免疫活化提供了体内LD形成的主要刺激。总之，我们的数据表明，巨噬细胞LD的形成是一个主机驱动的适应性免疫反应的M。提示巨噬细胞LD不是结核分枝杆菌的重要营养来源。结核结核分枝杆菌是结核病的病原体，每年造成的死亡人数超过任何其他单一的细菌病原体。M.结核病主要存在于巨噬细胞中，巨噬细胞是专门吞噬和杀死病原体的免疫细胞。为了在这种恶劣的环境中生存，M。结核病必须既能抵抗巨噬细胞的杀菌活性，又能利用巨噬细胞作为复制生态位。胞内细菌病原体从宿主细胞获得它们所有的营养，并且M.结核病在感染期间依赖脂质作为关键碳源。已经提出，脂滴，储存中性脂质的细胞器，并在M。结核感染，是M.结核此外，还认为M.结核病促使巨噬细胞产生LD作为致病策略。在这里，我们提出的证据表明，LD的形成实际上是一个程序化的巨噬细胞免疫反应，和更广泛的程序的一部分，IFN-γ激活巨噬细胞。此外，我们目前的数据解偶联细菌收购宿主脂质从巨噬细胞中存在的LD。因此，我们发现，除了支持免疫功能，LD也不太可能是M的重要营养来源。巨噬细胞中的结核病。
Lipid droplet (LD) formation occurs during infection of macrophages with numerous intracellular pathogens, including Mycobacterium tuberculosis. It is believed that M. tuberculosis and other bacteria specifically provoke LD formation as a pathogenic strategy in order to create a depot of host lipids for use as a carbon source to fuel intracellular growth. Here we show that LD formation is not a bacterially driven process during M. tuberculosis infection, but rather occurs as a result of immune activation of macrophages as part of a host defense mechanism. We show that an IFN-γ driven, HIF-1α dependent signaling pathway, previously implicated in host defense, redistributes macrophage lipids into LDs. Furthermore, we show that M. tuberculosis is able to acquire host lipids in the absence of LDs, but not in the presence of IFN-γ induced LDs. This result uncouples macrophage LD formation from bacterial acquisition of host lipids. In addition, we show that IFN-γ driven LD formation supports the production of host protective eicosanoids including PGE2 and LXB4. Finally, we demonstrate that HIF-1α and its target gene Hig2 are required for the majority of LD formation in the lungs of mice infected with M. tuberculosis, thus demonstrating that immune activation provides the primary stimulus for LD formation in vivo. Taken together our data demonstrate that macrophage LD formation is a host-driven component of the adaptive immune response to M. tuberculosis, and suggest that macrophage LDs are not an important source of nutrients for M. tuberculosis. Mycobacterium tuberculosis, the causative agent of the disease tuberculosis, causes more deaths annually than any other single bacterial pathogen. M. tuberculosis primarily lives in macrophages, immune cells which specialize in phagocytosing and killing pathogens. In order to survive this inhospitable environment, M. tuberculosis must be both resistant to the bactericidal activities of macrophages and able to exploit macrophages as a replicative niche. Intracellular bacterial pathogens acquire all of their nutrients from the host cell, and M. tuberculosis relies on lipids as a key carbon source during infection. It has been proposed that lipid droplets, organelles that store neutral lipids and are observed in macrophages during M. tuberculosis infection, are an accessible nutrient source for M. tuberculosis. Furthermore, it is thought that M. tuberculosis provokes macrophages into making LDs as a pathogenic strategy. Here, we present evidence that LD formation is actually a programmed macrophage immune response, and part of the broader program of IFN-γ activation of macrophages. Furthermore, we present data uncoupling bacterial acquisition of host lipids from the presence of LDs in macrophages. Thus, we find that in addition to supporting immune functions, LDs are also unlikely to be an important nutrient source for M. tuberculosis in macrophages.
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影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1084/jem.20080767
发表时间：
2008-11-24
期刊：
The Journal of experimental medicine
影响因子：
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作者：
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通讯作者：
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影响因子：
3.1
作者：
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通讯作者：
de Chastellier, Chantal
影响因子：
4.8
作者：
DiStefano, Marina T.;Danai, Laura V.;Czech, Michael P.
通讯作者：
Czech, Michael P.
DOI：
10.1016/j.bbalip.2013.10.008
发表时间：
2014-01-01
影响因子：
4.8
作者：
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通讯作者：
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