Ondari Edna, Wilkins Ashley, Latimer Brian, Dragoi Ana-Maria, Ivanov Stanimir S
Department of Microbiology and Immunology, Louisiana State University Health - Shreveport, Shreveport, LA 71130.
Innovative North Louisiana Experimental Therapeutics program (INLET), Feist-Weiller Cancer Center, Louisiana State University Health - Shreveport, Shreveport, LA 71130.
Microb Cell. 2022 Dec 6;10(1):1-17. doi: 10.15698/mic2023.01.789. eCollection 2023 Jan 2.
Host membranes are inherently critical for niche homeostasis of vacuolar pathogens. Thus, intracellular bacteria frequently encode the capacity to regulate host lipogenesis as well as to modulate the lipid composition of host membranes. One membrane component that is often subverted by vacuolar bacteria is cholesterol - an abundant lipid that mammalian cells produce at the endoplasmic reticulum (ER) or acquire exogenously from serum-derived lipoprotein carriers. is an accidental human bacterial pathogen that infects and replicates within alveolar macrophages causing a severe atypical pneumonia known as Legionnaires' disease. From within a unique ER-derived vacuole promotes host lipogenesis and experimental evidence indicates that cholesterol production might be one facet of this response. Here we investigated the link between cellular cholesterol and intracellular replication and discovered that disruption of cholesterol biosynthesis or cholesterol trafficking lowered bacterial replication in infected cells. These growth defects were rescued by addition of exogenous cholesterol. Conversely, bacterial growth within cholesterol-leaden macrophages was enhanced. Importantly, the growth benefit of cholesterol was observed strictly in cellular infections and growth kinetics in axenic cultures did not change in the presence of cholesterol. Microscopy analyses indicate that cholesterol regulates a step in intracellular lifecycle that occurs after bacteria begin to replicate within an established intracellular niche. Collectively, we provide experimental evidence that cellular cholesterol promotes replication within a membrane bound organelle in infected macrophages.
宿主膜对于液泡病原体的生态位稳态至关重要。因此，细胞内细菌通常具备调节宿主脂肪生成以及调节宿主膜脂质组成的能力。液泡细菌经常破坏的一种膜成分是胆固醇——一种丰富的脂质，哺乳动物细胞在内质网（ER）中产生或从血清来源的脂蛋白载体中获取。嗜肺军团菌是一种偶然感染人类的细菌病原体，它在肺泡巨噬细胞内感染并复制，导致一种称为军团病的严重非典型肺炎。在一个独特的内质网衍生的液泡内，嗜肺军团菌促进宿主脂肪生成，实验证据表明胆固醇生成可能是这种反应的一个方面。在这里，我们研究了细胞胆固醇与嗜肺军团菌细胞内复制之间的联系，发现胆固醇生物合成或胆固醇运输的破坏降低了感染细胞中细菌的复制。通过添加外源性胆固醇挽救了这些生长缺陷。相反，在富含胆固醇的巨噬细胞内细菌生长增强。重要的是，严格在细胞感染中观察到胆固醇的生长益处，并且在无菌培养物中嗜肺军团菌的生长动力学在胆固醇存在下没有变化。显微镜分析表明，胆固醇调节嗜肺军团菌细胞内生命周期中细菌开始在已建立的细胞内生态位内复制之后发生的一个步骤。总的来说，我们提供了实验证据，证明细胞胆固醇促进嗜肺军团菌在感染的巨噬细胞内的膜结合细胞器内复制。
