Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory & Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
PLoS Pathog. 2019 Jun 14;15(6):e1007879. doi: 10.1371/journal.ppat.1007879. eCollection 2019 Jun.
Burkholderia pseudomallei is a gram-negative, facultative intracellular bacterium, which causes a disease known as melioidosis. Professional phagocytes represent a crucial first line of innate defense against invading pathogens. Uptake of pathogens by these cells involves the formation of a phagosome that matures by fusing with early and late endocytic vesicles, resulting in killing of ingested microbes. Host Rab GTPases are central regulators of vesicular trafficking following pathogen phagocytosis. However, it is unclear how Rab GTPases interact with B. pseudomallei to regulate the transport and maturation of bacterial-containing phagosomes. Here, we showed that the host Rab32 plays an important role in mediating antimicrobial activity by promoting phagosome maturation at an early phase of infection with B. pseudomallei. And we demonstrated that the expression level of Rab32 is increased through the downregulation of the synthesis of miR-30b/30c in B. pseudomallei infected macrophages. Subsequently, we showed that B. pseudomallei resides temporarily in Rab32-positive compartments with late endocytic features. And Rab32 enhances phagosome acidification and promotes the fusion of B. pseudomallei-containing phagosomes with lysosomes to activate cathepsin D, resulting in restricted intracellular growth of B. pseudomallei. Additionally, Rab32 mediates phagosome maturation depending on its guanosine triphosphate/guanosine diphosphate (GTP/GDP) binding state. Finally, we report the previously unrecognized role of miR-30b/30c in regulating B. pseudomallei-containing phagosome maturation by targeting Rab32 in macrophages. Altogether, we provide a novel insight into the host immune-regulated cellular pathway against B. pseudomallei infection is partially dependent on Rab32 trafficking pathway, which regulates phagosome maturation and enhances the killing of this bacterium in macrophages.
类鼻疽伯克霍尔德菌是一种革兰氏阴性、兼性细胞内细菌，可引起类鼻疽病。专业吞噬细胞是抵御入侵病原体的先天防御的第一道重要防线。这些细胞摄取病原体涉及形成吞噬体，吞噬体通过与早期和晚期内吞小泡融合而成熟，从而杀死摄入的微生物。宿主 Rab GTPases 是吞噬细胞吞噬病原体后囊泡运输的核心调节剂。然而，尚不清楚 Rab GTPases 如何与类鼻疽伯克霍尔德菌相互作用，以调节含菌吞噬体的运输和成熟。在这里，我们表明宿主 Rab32 在介导抗微生物活性方面发挥重要作用，通过促进类鼻疽伯克霍尔德菌感染早期吞噬体成熟来介导。并且我们证明，在被类鼻疽伯克霍尔德菌感染的巨噬细胞中，miR-30b/30c 的合成下调会增加 Rab32 的表达水平。随后，我们表明类鼻疽伯克霍尔德菌暂时存在于具有晚期内吞特征的 Rab32 阳性隔室中。并且 Rab32 增强吞噬体酸化，并促进含类鼻疽伯克霍尔德菌的吞噬体与溶酶体融合，以激活组织蛋白酶 D，从而限制类鼻疽伯克霍尔德菌的细胞内生长。此外，Rab32 依赖其鸟嘌呤核苷酸三磷酸/鸟嘌呤二磷酸（GTP/GDP）结合状态来介导吞噬体成熟。最后，我们报告了 miR-30b/30c 通过靶向巨噬细胞中的 Rab32 来调节含类鼻疽伯克霍尔德菌吞噬体成熟的以前未被认识的作用。总之，我们提供了一个新的视角，即宿主免疫调节的细胞途径对抗类鼻疽伯克霍尔德菌感染部分依赖于 Rab32 运输途径，该途径调节吞噬体成熟并增强巨噬细胞中这种细菌的杀伤作用。
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