Francisella tularensis disrupts TLR2-MYD88-p38 signaling early during infection to delay apoptosis of macrophages and promote virulence in the host.
Francisella tularensis disrupts TLR2-MYD88-p38 signaling early during infection to delay apoptosis of macrophages and promote virulence in the host.
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土拉热弗朗西斯菌是一种人畜共患病原体，是引起兔热病的病原体。F.土拉热菌在巨噬细胞和其它宿主细胞的胞质溶胶内复制到高水平，同时破坏宿主对感染的反应。F的成功至关重要。土拉热是其延迟巨噬细胞凋亡以维持其细胞内复制生态位的能力。然而，受F.土拉菌延迟细胞凋亡的特征很差。外膜通道蛋白TolC是F.土拉菌毒力及其在巨噬细胞感染期间抑制细胞凋亡和细胞因子表达的能力。我们利用了F。土拉热菌TultolC突变体表型，以鉴定对激活巨噬细胞凋亡重要且被细菌破坏的宿主途径。用野生型或巨噬细胞感染的巨噬细胞的比较。tularensis的研究表明，细菌在感染后早期干扰TLR 2-MYD 88-p38信号传导，以延迟细胞凋亡，抑制先天宿主反应，并保持细胞内复制生态位。使用小鼠肺炎土拉菌模型的实验证实了这些发现的体内相关性，揭示了TLR 2和MYD 88信号传导对宿主对F.土拉热菌，它是由细菌调节，以提高毒力。土拉热弗朗西丝菌是一种革兰氏阴性胞内细菌病原体，是人畜共患病土拉菌病的病原体。F.土拉热菌与其他细胞内病原体一样，调节宿主程序性细胞死亡途径以确保其复制和存活。我们先前鉴定了外膜通道蛋白TolC作为F.土拉菌以延迟宿主细胞死亡。然而，F.尽管土拉热在发病机理中是关键的，但在细胞内复制期间延迟细胞死亡途径尚不清楚。在本研究中，我们利用F.土拉菌以揭示控制宿主对F.土拉热菌，并且在感染期间由细菌调节以促进毒力。这些发现揭示了细胞内病原体破坏宿主反应的机制，并增强了我们对兔热病发病机制的理解。
Francisella tularensis is a zoonotic pathogen and the causative agent of tularemia. F. tularensis replicates to high levels within the cytosol of macrophages and other host cells while subverting the host response to infection. Critical to the success of F. tularensis is its ability to delay macrophage apoptosis to maintain its intracellular replicative niche. However, the host-signaling pathway(s) modulated by F. tularensis to delay apoptosis are poorly characterized. The outer membrane channel protein TolC is required for F. tularensis virulence and its ability to suppress apoptosis and cytokine expression during infection of macrophages. We took advantage of the F. tularensis ∆tolC mutant phenotype to identify host pathways that are important for activating macrophage apoptosis and that are disrupted by the bacteria. Comparison of macrophages infected with wild-type or ∆tolC F. tularensis revealed that the bacteria interfere with TLR2-MYD88-p38 signaling at early times post infection to delay apoptosis, dampen innate host responses, and preserve the intracellular replicative niche. Experiments using the mouse pneumonic tularemia model confirmed the in vivo relevance of these findings, revealing contributions of TLR2 and MYD88 signaling to the protective host response to F. tularensis, which is modulated by the bacteria to promote virulence. Francisella tularensis is a Gram-negative intracellular bacterial pathogen and the causative agent of the zoonotic disease tularemia. F. tularensis, like other intracellular pathogens, modulates host-programmed cell death pathways to ensure its replication and survival. We previously identified the outer membrane channel protein TolC as required for the ability of F. tularensis to delay host cell death. However, the mechanism by which F. tularensis delays cell death pathways during intracellular replication is unclear despite being critical to pathogenesis. In the present study, we address this gap in knowledge by taking advantage of ∆tolC mutants of F. tularensis to uncover signaling pathways governing host apoptotic responses to F. tularensis and which are modulated by the bacteria during infection to promote virulence. These findings reveal mechanisms by which intracellular pathogens subvert host responses and enhance our understanding of the pathogenesis of tularemia.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
9
作者：
通讯作者：
--
影响因子：
3.1
作者：
Cole, Leah E.;Shirey, Kari Ann;Vogel, Stefanie N.
通讯作者：
Vogel, Stefanie N.
影响因子：
3.7
作者：
Abplanalp, Allison L.;Morris, Ian R.;Berton, Michael T.
通讯作者：
Berton, Michael T.
DOI：
10.1073/pnas.0602582103
发表时间：
2006-08-22
影响因子：
11.1
作者：
Gil, Horacio;Platz, Gabrielle J.;Thanassi, David G.
通讯作者：
Thanassi, David G.