Laboratory of Bacterial Infection, Graduate School of Infection Control Sciences, Kitasato University, Tokyo 108-8641, Japan.
J Exp Med. 2009 Dec 21;206(13):3073-88. doi: 10.1084/jem.20090494. Epub 2009 Dec 14.
The inflammatory response is one of several host alert mechanisms that recruit neutrophils from the circulation to the area of infection. We demonstrate that Bordetella, a bacterial pathogen, exploits an antiinflammatory cytokine, interleukin-10 (IL-10), to evade the host immune system. We identified a Bordetella effector, BopN, that is translocated into the host cell via the type III secretion system, where it induces enhanced production of IL-10. Interestingly, the BopN effector translocates itself into the nucleus and is involved in the down-regulation of mitogen-activated protein kinases. Using pharmacological blockade, we demonstrated that BopN-induced IL-10 production is mediated, at least in part, by its ability to block the extracellular signal-regulated kinase pathway. We also showed that BopN blocks nuclear translocation of nuclear factor kappaB p65 (NF-kappaBp65) but, in contrast, promotes nuclear translocation of NF-kappaBp50. A BopN-deficient strain was unable to induce IL-10 production in mice, resulting in the elimination of bacteria via neutrophil infiltration into the pulmonary alveoli. Furthermore, IL-10-deficient mice effectively eliminated wild-type as well as BopN mutant bacteria. Thus, Bordetella exploits BopN as a stealth strategy to shut off the host inflammatory reaction. These results explain the ability of Bordetella species to avoid induction of the inflammatory response.
炎症反应是宿主的几种警报机制之一，它能将中性粒细胞从循环系统募集到感染部位。我们发现，细菌病原体博德特氏菌会利用抗炎细胞因子白细胞介素-10（IL-10）来躲避宿主免疫系统。我们鉴定出一种博德特氏菌效应蛋白 BopN，它能通过 III 型分泌系统被转运到宿主细胞内，从而诱导 IL-10 的大量产生。有趣的是，BopN 效应蛋白能将自身转运到细胞核内，并参与下调丝裂原活化蛋白激酶。通过药理学阻断实验，我们证明 BopN 诱导的 IL-10 产生至少部分是通过阻断细胞外信号调节激酶途径来实现的。我们还发现，BopN 能阻断核转录因子 κB p65（NF-κBp65）的核转位，但相反地，它能促进 NF-κBp50 的核转位。BopN 缺陷株在小鼠体内无法诱导 IL-10 的产生，导致中性粒细胞浸润到肺泡中，从而消除了细菌。此外，IL-10 缺陷型小鼠能有效地清除野生型和 BopN 突变株细菌。因此，博德特氏菌利用 BopN 作为一种隐蔽策略来关闭宿主的炎症反应。这些结果解释了博德特氏菌属逃避诱导炎症反应的能力。
