The macrophage microtubule network acts as a key cellular controller of the intracellular fate of Leishmania infantum
The macrophage microtubule network acts as a key cellular controller of the intracellular fate of Leishmania infantum
复制标题
DOI：
10.1371/journal.pntd.0008396
复制
发表时间：
2020-07-01
影响因子：
3.8
通讯作者：
Lievin-Le Moal, Vanessa
中科院分区：
文献类型：
--
作者：
Cojean, Sandrine;Nicolas, Valerie;Lievin-Le Moal, Vanessa
作者概述利什曼原虫属的动体寄生虫可引起多种哺乳动物感染性疾病，包括皮肤、粘膜皮肤和粘膜病理。感染白纹伊蚊的雌性白纹伊蚊的感染性后循环前鞭毛体在吃白蚁血粉时被注射到被叮咬处的宿主体内，之后被宿主专业吞噬中性粒细胞和巨噬细胞内化。婴儿利什曼原虫是一种潜在致命内脏病理的病原体。本研究从分子水平上解剖了宿主巨噬细胞中含巨噬细胞的吞噬小体/寄生虫空泡(PV)的成熟过程。我们揭示了吞噬小体沿巨噬细胞微管轨迹移动所需的空泡运动，吞噬小体向内溶体途径运输是发育成熟的紧贴型PV所必需的，这对幼虫的生存和增殖至关重要。在宿主中，巨噬细胞是空泡室，其中前鞭毛体分化为无鞭毛体，无鞭毛体是寄生虫的复制形式，也更能抵抗宿主的反应。我们通过时间依赖的共聚焦激光多维成像分析，重新研究了紧密配合的PVs的生物发生，该PVs隔绝了婴儿乳杆菌感染的巨噬细胞样RAW 264.7细胞。细胞微管网络的药理解体和dynein基因的沉默导致幼年乳杆菌吞噬小体与晚期内小体和溶酶体的相互作用减弱，导致紧密配合的含有寄生虫的吞噬小体永远不能转化为成熟的PVs。对PVs内幼虫形态的分析表明，影响前鞭毛体-无鞭毛体分化的因素也可导致PVs的成熟受阻。这些发现突显了含巨噬细胞吞噬小体的MT依赖的相互作用与宿主巨噬细胞内溶酶体途径相互作用的重要性，以确保寄生虫的细胞内命运。
Author summary Kinetoplastid parasites of the genusLeishmaniaare responsible for a diverse spectrum of mammalian infectious diseases, the leishmaniases, including cutaneous, mucocutaneous, and mucosal pathologies. Infectious metacyclic promastigotes of infected female Phlebotomus sandflies are injected into the host at the site of the bite during the sandfly blood meal, after which they are internalized by host professional phagocytic neutrophils and macrophages.Leishmania infantumis an etiological agent of potentially fatal visceral pathology. This study molecularly dissects the maturation ofL.infantum-containing phagosomes/parasitophorous vacuoles (PVs) in host macrophages. We reveal the requirement of vacuolar movement along macrophage microtubule tracks for the phagosome trafficking toward the endolysosomal pathway necessary for the development of the mature tight-fitting PV crucial forL.infantumsurvival and proliferation.The parasitophorous vacuoles (PVs) that insulateLeishmania spp. in host macrophages are vacuolar compartments wherein promastigote forms differentiate into amastigote that are the replicative form of the parasite and are also more resistant to host responses. We revisited the biogenesis of tight-fitting PVs that insulateL.infantumin promastigote-infected macrophage-like RAW 264.7 cells by time-dependent confocal laser multidimensional imaging analysis. Pharmacological disassembly of the cellular microtubule network and silencing of the dynein gene led to an impaired interaction ofL.infantum-containing phagosomes with late endosomes and lysosomes, resulting in the tight-fitting parasite-containing phagosomes never transforming into mature PVs. Analysis of the shape of theL.infantumparasite within PVs, showed that factors that impair promastigote-amastigote differentiation can also result in PVs whose maturation is arrested. These findings highlight the importance of the MT-dependent interaction ofL.infantum-containing phagosomes with the host macrophage endolysosomal pathway to secure the intracellular fate of the parasite.