Direct and Indirect Impairment of Human Dendritic Cell Function by Virulent Francisella tularensis Schu S4
Direct and Indirect Impairment of Human Dendritic Cell Function by Virulent Francisella tularensis Schu S4
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DOI：
10.1128/iai.00879-08
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发表时间：
2009-01-01
影响因子：
3.1
通讯作者：
Bosio, Catharine M.
中科院分区：
文献类型：
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作者：
Chase, Jennifer C.;Celli, Jean;Bosio, Catharine M.
革兰氏阴性、兼性胞内细菌土拉热弗朗西丝菌在仅感染10个CFU后引起急性、致命的肺炎。这种细菌在人类中实现这一目标的机制尚不清楚。在这里，我们证明了致命的，A型F。土拉热菌菌株Schu S4在人骨髓树突细胞（DC）中有效感染和复制。尽管随着时间的推移呈指数复制，但在整个感染过程中，Schu S4未能刺激转化生长因子β、白细胞介素-10（IL-10）、IL-6、IL-1 β、IL-12、肿瘤坏死因子α、α干扰素（IFN-α）和IFN-β。Schu S4还抑制了直接感染的DC对不同Toll样受体激动剂的应答能力。此外，我们还观察到未感染的旁观者细胞的功能抑制。这种抑制是介导的，在一定程度上，由热稳定的细菌成分。来自Schu S4的脂多糖（LPS）存在于Schu S4条件培养基中。然而，Schu S4 LPS是弱炎症性的，并且在低于10 μ g/ml的浓度下不能诱导对DC的抑制，并且Schu S4 LPS的耗尽不能显著减轻Schu S4条件培养基在未感染的人DC中的抑制作用。总之，这些数据表明，A型F。土拉热干扰免疫系统的中心细胞类型DC在细胞内和细胞外警告宿主感染的能力。这表明F.土拉热活动的范围比以前认识到的更广、更全面。
The gram-negative, facultative intracellular bacterium Francisella tularensis causes acute, lethal pneumonic disease following infection with only 10 CFU. The mechanisms used by the bacterium to accomplish this in humans are unknown. Here, we demonstrate that virulent, type A F. tularensis strain Schu S4 efficiently infects and replicates in human myeloid dendritic cells (DCs). Despite exponential replication over time, Schu S4 failed to stimulate transforming growth factor beta, interleukin-10 (IL-10), IL-6, IL-1 beta, IL-12, tumor necrosis factor alpha, alpha interferon (IFN-alpha), and IFN-beta throughout the course of infection. Schu S4 also suppressed the ability of directly infected DCs to respond to different Toll-like receptor agonists. Furthermore, we also observed functional inhibition of uninfected bystander cells. This inhibition was mediated, in part, by a heat-stable bacterial component. Lipopolysaccharide (LPS) from Schu S4 was present in Schu S4-conditioned medium. However, Schu S4 LPS was weakly inflammatory and failed to induce suppression of DCs at concentrations below 10 mu g/ml, and depletion of Schu S4 LPS did not significantly alleviate the inhibitory effect of Schu S4-conditioned medium in uninfected human DCs. Together, these data show that type A F. tularensis interferes with the ability of a central cell type of the immune system, DCs, to alert the host of infection both intra-and extracellularly. This suggests that immune dysregulation by F. tularensis operates on a broader and more comprehensive scale than previously appreciated.