Control of lipid droplet homeostasis by Chlamydia

衣原体对脂滴稳态的控制

• 批准号: 10300188
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300188
• 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。 C.沙眼是细菌性性传播感染的最常见病原体， 细胞内的病原体，在一个叫做内含物的寄生液泡内复制。新生的包容性是 来源于宿主质膜，并作为衣原体控制相互作用的平台 与宿主微环境的关系为了在宿主细胞内生存，衣原体会清除营养物质和脂质 通过招募和融合不同的细胞区室值得注意的是，C.沙眼利用宿主脂肪酸 (FA)来促进它的成长。在真核细胞中，脂滴（LDs）是FA储存的主要区室 它们参与衣原体的细胞内发育。 C.沙眼衣原体使用多种策略从宿主获得资源，包括囊泡融合， 由SNARE蛋白介导[可溶性N-乙基马来酰亚胺敏感因子附着蛋白（SNAP）受体]。 特异性囊泡SNARE（v-SNARE）与其同源靶SNARE（t-SNARE）复合物的组装 形成一个稳定的四螺旋束提供了必要的能量来破坏和合并脂质双层， 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 采集我们最近发现两种SNARE蛋白质SNAP 23和Syntaxin 4与LD有关 衣原体感染期间的体内平衡。有趣的是，敲除SNAP 23或Syntaxin 4进一步增加了 衣原体诱导的LD的数量，但与衣原体复制的抑制相关。由于油酸 在野生型细胞中，（OA）产生的LD不会损害衣原体复制，这些结果表明， LD数的增加并不抑制衣原体后代发育。相反，它表明， 在感染期间产生LD的不同子集，这是SNARE依赖的，并且该LD的丢失 LD的不同子集和/或LD的不同子集的存在影响衣原体后代。在这里，我们建议测试 假设宿主和衣原体蛋白控制感染期间特定LD的体内平衡， 这有助于衣原体的复制。 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） 衣原体用于诱导和增选宿主LD的机制和（ii）进入潜在的分子机制 其他病原体利用这种机制来吸收这些细胞器。我们的研究结果将揭示这一关键的 被人类病原体广泛使用的未充分研究的途径。