Pseudomonas aeruginosa Effector ExoS Inhibits ROS Production in Human Neutrophils.
Pseudomonas aeruginosa Effector ExoS Inhibits ROS Production in Human Neutrophils.
复制标题
DOI：
10.1016/j.chom.2017.04.001
复制
发表时间：
2017-05-10
影响因子：
30.3
通讯作者：
Rietsch A
中科院分区：
文献类型：
--
作者：
Vareechon C;Zmina SE;Karmakar M;Pearlman E;Rietsch A
中性粒细胞是抵御细菌感染的第一道防线，而活性氧的产生是中性粒细胞武器库的关键部分。病原体使用解毒系统来避免活性氧类的杀菌作用。在这里，我们证明了革兰氏阴性病原菌铜绿假单胞菌对活性氧物种敏感，但通过两种分泌的III型效应蛋白EXOS和ExoT有效地阻止了活性氧物种的爆发。EXOS ADP-核糖化RAS并阻止其与磷酸肌醇-3-激酶(PI3K)相互作用和激活，PI3K是刺激吞噬细胞的NADPH-氧化酶产生活性氧物种所必需的。ExoT也通过其ADP-核糖基转移酶活性影响PI3K信号，但不直接作用于RAS。RAS的一种非核糖化版本可以恢复活性氧物种的产生，并导致细菌杀灭增加。这些发现表明，宿主先天免疫反应的颠覆需要EXOS介导的中性粒细胞中RAS的ADP核糖化。中性粒细胞产生的活性氧(ROS)是一种关键的抗菌防御手段。Vareechon等人。研究表明，铜绿假单胞菌分泌的两种III型效应物EXOS和ExoT独立地阻断中性粒细胞产生ROS。EXOS ADP-核糖化RAS，阻止与PI3K结合，从而阻止NADPH氧化酶激活和ROS产生。
Neutrophils are the first line of defense against bacterial infections, and the generation of reactive oxygen species is a key part of their arsenal. Pathogens use detoxification systems to avoid the bactericidal effects of reactive oxygen species. Here we demonstrate that the Gram-negative pathogen Pseudomonas aeruginosa is susceptible to reactive oxygen species but actively blocks the reactive oxygen species burst using two type III secreted effector proteins, ExoS and ExoT. ExoS ADP-ribosylates Ras and prevents it from interacting with and activating phosphoinositol-3-kinase (PI3K), which is required to stimulate the phagocytic NADPH-oxidase that generates reactive oxygen species. ExoT also affects PI3K signaling via its ADP-ribosyltransferase activity but does not act directly on Ras. A non-ribosylatable version of Ras restores reactive oxygen species production and results in increased bacterial killing. These findings demonstrate that subversion of the host innate immune response requires ExoS-mediated ADP-ribosylation of Ras in neutrophils. Reactive oxygen species (ROS) production by neutrophils is a key antimicrobial defense. Vareechon et al. show that two type III secreted effectors of Pseudomonas aeruginosa, ExoS and ExoT, independently block ROS production by neutrophils. ExoS ADP-ribosylates Ras, which prevents binding to PI3K, thereby blocking NADPH oxidase activation and ROS production.