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中文摘要
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项目摘要/摘要 立克次体是导致严重疾病的专性细胞内细菌病原体,如斑点 发烧和斑疹伤寒。我们研究了模式斑点热群(SFG)物种帕氏立克次体,它引起了一种 与焦痂相关的人类立克次体病,在实验上是容易治疗的,并且有新出现的小鼠模型 致病机制,使其成为揭示SFG立克次体感染和毒力的分子机制的理想工具。 在感染期间,SFG立克次体通过动员肌动蛋白细胞骨架入侵宿主细胞,逃离 吞噬小体进入胞浆,在避免自噬降解的同时复制,并利用肌动蛋白 促进细胞内运动和细胞间扩散的聚合作用。然而,在以下方面存在着根本的差距 我们对SFG立克次体利用或破坏宿主细胞成分的分子机制的了解 以促进它们的感染周期。为了弥合这些差距,在当前的资助期内,我们率先推出了 细菌遗传学和宿主细胞生物学的创新组合,以确定关键立克次体因子, 操纵宿主细胞。在未发表的工作中,我们发现外膜蛋白OmpB对 入侵和避免自噬。我们还观察到Patatin样磷脂酶Pat1在 吞噬小体逃逸和/或自噬逃避。此外,在出版的作品中,我们证明了 立克次体使用两个肌动蛋白聚合的表面蛋白来指导运动的顺序阶段-与RickA 驱动早期运动和表面细胞抗原sca2驱动晚期运动。然而,关键悬而未决的问题 仍然存在的问题,包括:立克次体如何利用宿主受体促进入侵?立克次体是如何退化的 吞噬体膜逃逸或抑制膜吞噬以避免自噬?又是如何做到的 立克次体在运动的不同阶段协调和使用两个肌动蛋白组装因子?我们的初选和 已发表的研究结果表明,OmpB、Pat1、RickA和SCA2是多功能的总体假设 动员或破坏宿主细胞成分并在体内感染中起关键作用的蛋白质。这 假说将在三个目标上进行检验,重点是揭示OmpB,Pat1, RickA和sca2影响细胞的侵袭、细胞内存活和运动。其目的是:(1)确定 立克次体表面蛋白OmpB在侵袭和细胞内存活中的作用(2)研究Pat1的作用 磷脂酶在吞噬小体逃逸和细胞内存活中的作用;以及(3)决定立克次体如何和为什么使用 两种截然不同的基于肌动蛋白的运动机制。拟议的研究将通过揭示关键的 立克次体和其他病原体操纵宿主细胞的分子机制及其重要性 这些机制导致了传染性。我们的研究也可能带来改善的诊断和治疗 立克次体和其他感染。
英文摘要
PROJECT SUMMARY/ABSTRACT The Rickettsiae are obligate intracellular bacterial pathogens that cause serious diseases, such as spotted fever and typhus. We study the model spotted fever group (SFG) species Rickettsia parkeri, which causes an eschar-associated human rickettsiosis, is experimentally tractable, and has emerging mouse models of pathogenesis, making it ideal for revealing molecular mechanisms of SFG Rickettsia infection and virulence. During infection, SFG Rickettsia invade host cells by mobilizing the actin cytoskeleton, escape from the phagosome into the cytosol, replicate while avoiding degradation by autophagy, and harness actin polymerization to promote intracellular motility and cell-cell spread. However, there are fundamental gaps in our knowledge of the molecular mechanisms by which SFG Rickettsia exploit or disrupt host cell components to promote their infection cycle. To bridge these gaps, in the current funding period we have pioneered an innovative combination of bacterial genetics and host cell biology to identify key Rickettsia factors that manipulate host cells. In unpublished work, we discovered that outer membrane protein OmpB is crucial for both invasion and avoidance of autophagy. We also observed that patatin-like phospholipase Pat1 plays a role in phagosome escape and/or autophagy evasion. Additionally, in published work, we demonstrated that Rickettsia use two actin-polymerizing surface proteins to direct sequential phases of motility – with RickA driving early motility and surface cell antigen Sca2 driving late motility. However, key outstanding questions remain, including: How do Rickettsia engage host receptors to promote invasion? How do Rickettsia degrade membranes during phagosome escape or inhibit membrane engulfment to avoid autophagy? And how do Rickettsia coordinate and use two actin assembly factors in distinct phases of motility? Our preliminary and published findings suggest the overall hypothesis that OmpB, Pat1, RickA, and Sca2 are multifunctional proteins that mobilize or disrupt host cell components and play a crucial role in infection in vivo. This hypothesis will be tested in three Aims focused on uncovering the mechanisms through which OmpB, Pat1, RickA, and Sca2 influence invasion, intracellular survival, and motility. The Aims are to: (1) define the role of Rickettsia surface protein OmpB in invasion and intracellular survival; (2) investigate the role of Pat1 phospholipase in phagosome escape and intracellular survival; and (3) determine how and why Rickettsia use two distinct actin-based motility mechanisms. The proposed studies will advance the field by revealing crucial molecular mechanisms used by Rickettsia and other pathogens to manipulate host cells and the importance of these mechanisms to infectivity. Our studies may also lead to improved diagnostics and treatments for rickettsial and other infections.
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会议论文
Exploring the role of type I interferon in Rickettsia pathogenesis
Exploring the role of type I interferon in Rickettsia pathogenesis
Microbial mobilization of the actin cytoskeleton
Microbial mobilization of the actin cytoskeleton
  • 批准号:
    10623626
  • 项目类别:
  • 资助金额:
    $47.67万
  • 财政年份:
    2018
  • 负责人:
    Matthew D Welch
  • 依托单位:
海外基金