Long-distance delivery of bacterial virulence factors by Pseudomonas aeruginosa outer membrane vesicles.
Long-distance delivery of bacterial virulence factors by Pseudomonas aeruginosa outer membrane vesicles.
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DOI：
10.1371/journal.ppat.1000382
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发表时间：
2009-04
期刊：
影响因子：
6.7
通讯作者：
Stanton BA
中科院分区：
文献类型：
--
作者：
Bomberger JM;Maceachran DP;Coutermarsh BA;Ye S;O'Toole GA;Stanton BA
细菌利用多种分泌的毒力因子操纵宿主细胞，从而引起显著的发病率和死亡率。我们报告了一种长距离传递多种细菌毒力因子的机制，同时直接进入宿主细胞质，从而避免了病原体与宿主细胞直接相互作用引起细胞毒性的需要。我们发现，由人类机会致病菌铜绿假单胞菌分泌的外膜衍生囊泡（OMV）通过OMV与宿主质膜中的脂筏融合，将多种毒力因子（包括β-内酰胺酶、碱性磷酸酶、溶血性磷脂酶C和Cif）直接递送到宿主细胞质中。这些毒力因子通过N-WASP介导的肌动蛋白运输进入宿主细胞的细胞质，在那里它们迅速分布到特定的亚细胞位置以影响宿主细胞生物学。我们提出分泌的毒力因子不是单独作为裸蛋白释放到周围环境中，在那里它们可以随机接触宿主细胞的表面，而是细菌衍生的OMV以协调的方式同时并直接将多个毒力因子递送到宿主细胞质中。革兰氏阴性病原体每年造成200万例医院获得性感染，大大增加了美国的医疗费用。铜绿假单胞菌是一种人类机会致病菌，通常与医院感染有关，特别是囊性纤维化、慢性阻塞性肺病、呼吸机相关肺炎、社区获得性肺炎和支气管扩张等免疫功能低下患者的呼吸机相关感染和假单胞菌肺炎。我们已经确定了革兰氏阴性菌用于战略性地将毒素递送至宿主以促进细菌毒力和宿主定植的分泌系统的机制，我们希望以此为目标开发治疗铜绿假单胞菌感染的新疗法。我们的研究结果对革兰氏阴性菌致病机制的研究具有重要意义。我们提出，分泌的毒力因子不是单独释放到周围环境中，在那里他们可能会随机接触宿主细胞的表面的裸蛋白，而是细菌衍生的外膜囊泡（OMV）提供多种毒力因子同时和直接进入宿主细胞质中的协调方式。这种通过OMV与宿主的长距离细菌通讯让人想起了真核细胞之间通过外泌体传递信号蛋白和miRNA，并且可能代表病原体和宿主使用的一般蛋白质分泌策略。
Bacteria use a variety of secreted virulence factors to manipulate host cells, thereby causing significant morbidity and mortality. We report a mechanism for the long-distance delivery of multiple bacterial virulence factors, simultaneously and directly into the host cell cytoplasm, thus obviating the need for direct interaction of the pathogen with the host cell to cause cytotoxicity. We show that outer membrane–derived vesicles (OMV) secreted by the opportunistic human pathogen Pseudomonas aeruginosa deliver multiple virulence factors, including β-lactamase, alkaline phosphatase, hemolytic phospholipase C, and Cif, directly into the host cytoplasm via fusion of OMV with lipid rafts in the host plasma membrane. These virulence factors enter the cytoplasm of the host cell via N-WASP–mediated actin trafficking, where they rapidly distribute to specific subcellular locations to affect host cell biology. We propose that secreted virulence factors are not released individually as naked proteins into the surrounding milieu where they may randomly contact the surface of the host cell, but instead bacterial derived OMV deliver multiple virulence factors simultaneously and directly into the host cell cytoplasm in a coordinated manner. Gram-negative pathogens are responsible for 2 million annual hospital-acquired infections, adding tremendously to U.S. healthcare costs. Pseudomonas aeruginosa, an opportunistic human pathogen, is commonly associated with nosocomial infections, particularly ventilator-associated infections and pseudomonal pneumonia in immunocompromised patients with cystic fibrosis, chronic obstructive pulmonary disease, ventilator-associated pneumonia, community-acquired pneumonia, and bronchiectasis. We have identified the mechanism for a secretion system that Gram-negative bacteria use to strategically deliver toxins to the host to promote bacterial virulence and host colonization, a pathway that we hope to target to develop new therapies to treat P. aeruginosa infections. Our findings have significant implications for the study of Gram-negative bacterial pathogenesis. We propose that secreted virulence factors are not released individually as naked proteins into the surrounding milieu where they may randomly contact the surface of the host cell, but instead bacterial-derived outer membrane vesicles (OMV) deliver multiple virulence factors simultaneously and directly into the host cell cytoplasm in a coordinated manner. This long-distance bacterial communication to the host via OMV is reminiscent of the delivery of signaling proteins and miRNA between eukaryotic cells via exosomes, and may represent a general protein secretion strategy used by both pathogen and host.
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影响因子：
5.5
作者：
Bebok, Z;Collawn, JF;Clancy, JP
通讯作者：
Clancy, JP
影响因子：
4.8
作者：
Pike, LJ;Han, XL;Gross, RW
通讯作者：
Gross, RW
影响因子：
4.8
作者：
Butterworth, Michael B.;Edinger, Robert S.;Frizzell, Raymond A.
通讯作者：
Frizzell, Raymond A.
影响因子：
4.8
作者：
Luberto, C;Stonehouse, MJ;Hannun, YA
通讯作者：
Hannun, YA
DOI：
10.1093/jmicro/52.5.465
发表时间：
2003-01-01
期刊：
JOURNAL OF ELECTRON MICROSCOPY
影响因子：
--
作者：
Nguyen, TT;Saxena, A;Beveridge, TJ
通讯作者：
Beveridge, TJ