Abstract：
Peroxisomes are organelles involved in many metabolic processes including lipid metabolism, reactive oxygen species (ROS) turnover, and antimicrobial immune responses. However, the cellular mechanisms by which peroxisomes contribute to bacterial elimination in macrophages remain elusive. Here, we investigated peroxisome function in iPSC-derived human macrophages (iPSDM) during infection with Mycobacterium tuberculosis (Mtb). We discovered that Mtb-triggered peroxisome biogenesis requires the ESX-1 type 7 secretion system, critical for cytosolic access. iPSDM lacking peroxisomes were permissive to Mtb wild-type (WT) replication but were able to restrict an Mtb mutant missing functional ESX-1, suggesting a role for peroxisomes in the control of cytosolic but not phagosomal Mtb. Using genetically encoded localization-dependent ROS probes, we found peroxisomes increased ROS levels during Mtb WT infection. Thus, human macrophages respond to the infection by increasing peroxisomes that generate ROS primarily to restrict cytosolic Mtb. Our data uncover a peroxisome-controlled, ROS-mediated mechanism that contributes to the restriction of cytosolic bacteria.
摘要：
过氧化物酶体是参与许多代谢过程的细胞器，包括脂质代谢，活性氧（ROS）周转，和抗菌免疫反应。然而,过氧化物酶体有助于巨噬细胞中细菌消除的细胞机制仍然难以捉摸。这里,我们研究了在结核分枝杆菌(Mtb)感染期间iPSC衍生的人巨噬细胞(iPSDM)中的过氧化物酶体功能.我们发现Mtb触发的过氧化物酶体生物发生需要ESX-17型分泌系统，对于细胞溶质访问至关重要。缺乏过氧化物酶体的iPSDM允许Mtb野生型（WT）复制，但能够限制缺少功能ESX-1的Mtb突变体，这表明过氧化物酶体在控制胞质而不是吞噬体Mtb中的作用。使用基因编码的定位依赖性ROS探针，我们发现过氧化物酶体在MtbWT感染期间增加了ROS水平。因此，人类巨噬细胞通过增加主要产生ROS以限制细胞溶质Mtb的过氧化物酶体来应答感染。我们的数据揭示了过氧化物酶体控制，ROS介导的机制，有助于限制细胞溶质细菌。
