The Obligate Intracellular Bacterial Pathogen Anaplasma phagocytophilum Exploits Host Cell Multivesicular Body Biogenesis for Proliferation and Dissemination.
The Obligate Intracellular Bacterial Pathogen Anaplasma phagocytophilum Exploits Host Cell Multivesicular Body Biogenesis for Proliferation and Dissemination.
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嗜吞噬细胞无形体是新出现的感染——粒细胞无形体病的病原体。这种专性细胞内细菌生活在宿主细胞衍生的液泡中，该液泡接收来自多个细胞器的膜运输以促进其增殖，并且最终必须从液泡中退出以传播感染。对这些基本致病机制的了解仍然很少。多囊泡体 (MVB) 是晚期内体区室，它接收来自其他细胞器的生物分子，并使用运输 (ESCRT) 机械和 ESCRT 独立机械所需的内体分选复合物将它们封装到腔内囊泡 (ILV) 中。 ESCRT 独立蛋白 ALIX 的结合将 MVB 引导至质膜，在那里它们以外泌体的形式释放 ILV。我们报告说，A. phagocytophilum 液泡 (ApV) 被酸化并富含溶双磷脂酸，这是一种在 MVB 中含量丰富的脂质。 ESCRT-0 和 ESCRT-III 组件以及 ALIX 定位于 ApV 膜。 siRNA 介导的 ESCRT-0 和 ALIX 失活共同损害嗜吞噬细胞放线菌的增殖和感染性后代的产生。 ESCRT-III 的 RNA 沉默可调节 ILV 分裂，显着减少 ApV 中 ILV 的形成，并通过阻止细菌生长来阻止感染。 Rab27a 及其效应子 Munc13-4 定位于 ApV，驱动 MVB 运输至质膜并随后释放外泌体。 Nexinhib20（一种专门针对 Rab27a 的小分子抑制剂，可阻断 MVB 胞吐作用）治疗可消除嗜吞噬细胞曲霉传染性子代的释放。因此，A. phagocytophilum 利用 MVB 生物合成和外泌体释放来有益于其细胞内感染周期的每个主要阶段：液泡内生长、转化为感染形式以及从宿主细胞中退出。
Anaplasma phagocytophilum is the etiologic agent of the emerging infection, granulocytic anaplasmosis. This obligate intracellular bacterium lives in a host cell-derived vacuole that receives membrane traffic from multiple organelles to fuel its proliferation and from which it must ultimately exit to disseminate infection. Understanding of these essential pathogenic mechanisms has remained poor. Multivesicular bodies (MVBs) are late endosomal compartments that receive biomolecules from other organelles and encapsulate them into intralumenal vesicles (ILVs) using endosomal sorting complexes required for transport (ESCRT) machinery and ESCRT-independent machinery. Association of the ESCRT-independent protein, ALIX, directs MVBs to the plasma membrane where they release ILVs as exosomes. We report that the A. phagocytophilum vacuole (ApV) is acidified and enriched in lysobisphosphatidic acid, a lipid that is abundant in MVBs. ESCRT-0 and ESCRT-III components along with ALIX localize to the ApV membrane. siRNA-mediated inactivation of ESCRT-0 and ALIX together impairs A. phagocytophilum proliferation and infectious progeny production. RNA silencing of ESCRT-III, which regulates ILV scission, pronouncedly reduces ILV formation in ApVs and halts infection by arresting bacterial growth. Rab27a and its effector Munc13-4, which drive MVB trafficking to the plasma membrane and subsequent exosome release, localize to the ApV. Treatment with Nexinhib20, a small molecule inhibitor that specifically targets Rab27a to block MVB exocytosis, abrogates A. phagocytophilum infectious progeny release. Thus, A. phagocytophilum exploits MVB biogenesis and exosome release to benefit each major stage of its intracellular infection cycle: intravacuolar growth, conversion to the infectious form, and exit from the host cell.
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