Coxiella burnettii survival in THP-1 monocytes involves the impairment of phagosome maturation:: IFN-γ mediates its restoration and bacterial killing
Coxiella burnettii survival in THP-1 monocytes involves the impairment of phagosome maturation:: IFN-γ mediates its restoration and bacterial killing
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DOI：
10.4049/jimmunol.169.8.4488
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发表时间：
2002-10-15
影响因子：
4.4
通讯作者：
Mege, JL
中科院分区：
文献类型：
--
作者：
Ghigo, E;Capo, C;Mege, JL
细胞内病原体对巨噬细胞杀菌功能的破坏是其生存和致病的关键。Q热病原体贝氏柯克斯体在非吞噬细胞的酸性吞噬溶酶体中的复制被认为是细菌细胞内生活的范例。我们在这项研究中表明，C。贝氏体在THP-1单核细胞中的存活与吞噬体pH无关，因为细菌空泡是酸性的，与C.贝氏菌毒力相反，强毒C.贝氏虫通过阻止吞噬体成熟而逃避对静息THP-1细胞的杀伤。的确，C。贝氏菌空泡不与溶酶体融合，因为它们缺乏组织蛋白酶D，并且不积累溶酶体示踪物;晚期内体和晚期内体-早期溶酶体的标记物的获得是保守的。相反，C.贝氏体被单核细胞清除，其空泡积累晚期内体和溶酶体标记物。毒力C. THP-1单核细胞中的贝氏体依赖于细胞活化。IFN-γ激活单核细胞恢复了C.通过共定位C.具有活性组织蛋白酶D的buruetii。此外，当IFN-γ在细胞感染前加入时，它能够刺激C。burnetii杀死，但也诱导液泡碱化。这些发现表明IFN-γ介导C.通过两种不同的机制（吞噬体成熟和吞噬体碱化）杀死贝氏体。因此，液泡生物发生的调节可能是C.贝氏体存活和Q热的病理生理学。
The subversion of microbicidal functions of macrophages by intracellular pathogens is critical for their survival and pathogenicity. The replication of Coxiella burnetii, the agent of Q fever, in acidic phagolysosomes of nonphagocytic cells has been considered as a paradigm of intracellular life of bacteria. We show in this study that C. burnetii survival in THP-1 monocytes was not related to phagosomal pH because bacterial vacuoles were acidic independently of C. burnetii virulence. In contrast, virulent C. burnetii escapes killing in resting THP-1 cells by preventing phagosome maturation. Indeed, C. burnetii vacuoles did not fuse with lysosomes because they were devoid of cathepsin D, and did not accumulate lysosomal trackers; the acquisition of markers of late endosomes and late endosomes-early lysosomes was conserved. In contrast, avirulent variants of C. burnetii were eliminated by monocytes and their vacuoles accumulated late endosomal and lysosomal markers. The fate of virulent C. burnetii in THP-1 monocytes depends on cell activation. Monocyte activation by IFN-gamma restored C. burnetii killing and phagosome maturation as assessed by colocalization of C. buruetii with active cathepsin D. In addition, when IFN-gamma was added before cell infection, it was able to stimulate C. burnetii killing but it also induced vacuolar alkalinization. These findings suggest that IFN-gamma mediates C. burnetii killing via two distinct mechanisms, phagosome maturation, and phagosome alkalinization. Thus, the tuning of vacuole biogenesis is likely a key part of C. burnetii survival and the pathophysiology of Q fever.