Control of lipid droplet homeostasis by Chlamydia

衣原体对脂滴稳态的控制

• 批准号: 10439872
• 负责人: FABIENNE Michelle PAUMET
• 金额: $ 7.8万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439872
• 关键词: Address; Affect; Antibiotic Resistance; Antibiotics; Bacteria; Binding; Biology; Blindness; Cell membrane; Cells; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Cholesterol Esters; Complex; Data; Development; Disease; Disease Progression; Enzymes; Eukaryotic Cell; Event; Fatty Acids; Generations; Gram-Negative Bacteria; Growth; Homeostasis; Infection; Light; Lipid Bilayers; Lipids; Mediating; Membrane; Membrane Fusion; Modification; Molecular; Nutrient; Oleic Acids; Organelles; Parasites; Pathway interactions; Play; Proteins; Recovery; Regulation; Resources; Role; SNAP receptor; SNAP23 gene; Sexually Transmitted Diseases; Sterols; Structure; Testing; Therapeutic; Vacuole; Vesicle; Virus; cell type; cellubrevin; fitness; human pathogen; insight; interest; knock-down; new therapeutic target; pathogen; protein complex; recruit; target SNARE proteins; therapeutic target; tool; vesicular SNARE proteins

PROJECT SUMMARY. C. trachomatis, the most common agent of bacterial sexually-transmitted infections, is an obligate intracellular pathogen that replicates inside a parasitic vacuole called the inclusion. The nascent inclusion is derived from the host plasma membrane and serves as a platform from which Chlamydia controls interactions with the host microenvironment. To survive inside the host cell, Chlamydia scavenges for nutrients and lipids by recruiting and fusing with various cellular compartments. Notably, C. trachomatis utilizes host fatty acids (FA) to promote its growth. In eukaryotic cells, lipid droplets (LDs) are the primary compartment for FA storage and they are involved in the intracellular development of Chlamydia. C. trachomatis acquires resources from the host using multiple strategies, including vesicle fusion, which is mediated by SNARE proteins [Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) Receptor]. The assembly of a specific vesicular SNARE (v-SNARE) with its cognate target SNARE (t-SNARE) complex into a stable four-helix bundle provides the energy necessary to disrupt and merge lipid bilayers during membrane fusion. Chlamydia has been shown to co-opt specific SNARE-mediated pathways to control lipid acquisition. We have recently shown that two SNARE proteins, SNAP23, and Syntaxin4, are involved in LD homeostasis during Chlamydia infection. Interestingly, knocking down SNAP23 or Syntaxin4 further increases the number of Chlamydia-induced LDs, but correlates with inhibition of Chlamydia replication. Since oleic acid (OA)-generated LDs in wild-type cells do not impair Chlamydia replication, these results suggest that a mere increase in LD number is not responsible for inhibiting Chlamydia progeny development. Instead, it suggests that a distinct subset of LDs is generated during infection, which is SNARE-dependent, and that loss of this LD subset and/or the presence of a different subset of LDs impacts Chlamydia progeny. Here, we propose to test the hypothesis that host and chlamydial proteins control the homeostasis of specific LDs during infection, which contributes to Chlamydia replication. Ultimately, this information will have a broad scientific impact as it will provide new insights (i) into the mechanisms used by Chlamydia to induce and co-opt host LDs and (ii) into the potential molecular mechanisms used by other pathogens to co-opt these organelles. Our results will shed light on this critical understudied pathway that is widely used by human pathogens.

项目摘要。 沙眼衣原体是细菌性传播感染的最常见病原体，是一种专性病原体。 细胞内病原体在称为包涵体的寄生液泡内复制。新生的包含物是 源自宿主质膜，作为衣原体控制相互作用的平台 与宿主微环境。为了在宿主细胞内生存，衣原体会清除营养物质和脂质 通过招募并与各种细胞区室融合。值得注意的是，沙眼衣原体利用宿主脂肪酸 (FA) 促进其成长。在真核细胞中，脂滴 (LD) 是 FA 储存的主要隔室 它们参与衣原体的细胞内发育。 沙眼衣原体使用多种策略从宿主获取资源，包括囊泡融合，这是 由 SNARE 蛋白 [可溶性 N-乙基马来酰亚胺敏感因子附着蛋白 (SNAP) 受体] 介导。 特定囊泡 SNARE (v-SNARE) 与其同源目标 SNARE (t-SNARE) 复合体的组装 成稳定的四螺旋束提供了破坏和合并脂质双层所需的能量 膜融合。衣原体已被证明可以选择特定的 SNARE 介导的途径来控制脂质 获得。我们最近发现两种 SNARE 蛋白 SNAP23 和 Syntaxin4 参与 LD 衣原体感染期间的稳态。有趣的是，敲除 SNAP23 或 Syntaxin4 进一步增加 衣原体诱导的 LD 数量，但与衣原体复制的抑制相关。由于油酸 (OA) 在野生型细胞中产生的 LD 不会损害衣原体复制，这些结果表明仅仅 LD 数量的增加并不抑制衣原体后代的发育。相反，它建议 感染期间会生成 LD 的一个独特子集，该子集依赖于 SNARE，并且该 LD 的丢失 LD 子集和/或不同子集的存在会影响衣原体后代。在这里，我们建议测试一下 宿主和衣原体蛋白在感染过程中控制特定 LD 稳态的假设， 这有助于衣原体复制。 最终，这些信息将产生广泛的科学影响，因为它将提供新的见解（i） 衣原体用于诱导和选择宿主 LD 的机制，以及 (ii) 进入潜在的分子 其他病原体利用这些细胞器的机制。我们的结果将揭示这一关键问题 人类病原体广泛使用的未被充分研究的途径。