Control of lipid droplet homeostasis by Chlamydia

项目总结。 沙眼衣原体是细菌性传播感染的最常见病原体，是一种必需的 在被称为包涵体的寄生空泡内复制的细胞内病原体。新纳入的内容是 来源于宿主质膜，是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，衣原体寻找营养物质和脂肪 通过招募和融合不同的细胞隔间。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，脂滴是储存FA的主要隔室 它们参与了衣原体在细胞内的发育。 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。 一种特殊的水泡陷阱(v-SNARE)与其同源靶标(T-SNARE)复合体的组装 形成稳定的四股螺旋束，提供了破坏和合并脂质双层所需的能量 膜融合。衣原体已经被证明选择了特定的圈套介导的途径来控制血脂 收购。我们最近发现两种SNARE蛋白SNAP23和Synaxin4与LD有关 衣原体感染期间的动态平衡。有趣的是，下调SNAP23或Synaxin4会进一步增加 衣原体诱导的LDS的数量，但与抑制衣原体复制有关。由于油酸 (OA)在野生型细胞中产生的LDS不会损害衣原体的复制，这些结果表明，仅仅 LD数量的增加并不是抑制衣原体后代发育的原因。相反，它表明， 在感染期间产生依赖于圈套一个不同的LD子集，以及该LD的丢失 LDS的子集和/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 宿主和衣原体蛋白在感染过程中控制特定LDS的动态平衡的假说， 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，因为它将提供对 衣原体诱导和共选宿主LDS和(Ii)进入潜在分子的机制 其他病原体利用这些细胞器的机制。我们的结果将阐明这一关键问题 被人类病原体广泛使用的未被研究的途径。

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.