Rickettsia-host interface and multiple paths to invasion

立克次体感染的全球影响从长期已知的 病原体，以及新发现的病原体的出现。感染： 里氏立克次体(落基山斑点热病)在#年继续流行，后果严重。 南美洲和中美洲。年康诺里杆菌(地中海斑点热病)卷土重来 欧洲、中东和非洲，以及最近全球范围内小鼠斑疹伤寒(R. 伤寒杆菌)，突出了立克次体疾病的威胁。尽管对公众健康的重要性 致病立克次体，我们对立克次体生物学的有限知识一直是一个 这是朝着更有效的干预方式取得进展的障碍。我们的系统发育学 分析强调了立克次体基因组的相当大的变异，提供了一种 将特定的基因类型与其相关的疾病表型联系起来的框架。对于几个人来说 在普遍的立克次体过程中已被表征的真正的分泌蛋白 (即宿主细胞的黏附、侵袭和细胞内的生长和存活)，一个斑驳的基因组 分布表明，支撑这些过程的机制是内在的 立克次体各不相同。例如，我们最近在斑疹伤寒(斑疹伤寒群)上的工作 发现了一种新的invasin，Ralf，它在依赖于宿主的过程中与宿主Arf6相互作用 磷脂酰肌醇PIP2。奇怪的是，斑点热病的物种中缺少Ralf基因 组(SFG)。相反，SFG的两个特性良好的表面蛋白(Sca0和Sca2) 在非SFG立克次体中，病原体要么不存在(Sca0)，要么高度分化(Sca2)。 因此，立克次体侵袭宿主细胞的机制比以前更加复杂 赞赏，因此有必要采用比较的方法来调查 支持发病的因素。根据这项建议，我们的工作将集中于确定 Sca3和Sca2(d-sca2)蛋白的哺乳动物和无脊椎动物宿主细胞靶标 来自非SFG物种(目标1)。此外，我们将调查非 SFG物种触发磷脂酰肌醇(PIP)代谢，促进膜褶皱和 立克次体内吞作用，早期内吞体上存在已鉴定的宿主蛋白和PIP 进一步探索作为介导噬菌体的立克次体磷脂酶的对接位置 逃生(目标2)。这项工作的成功结果将为如何 不同的立克次体利用不同的分子实现普遍的立克次体 通过诱导吞噬作用感染宿主细胞质的过程。我们预料到了这一点 提供针对疾病的治疗方法以对抗致命性立克次体的知识。

The global impact of rickettsial infections is illustrated by the resurgence of long-known pathogens, as well as the emergence of newly recognized pathogens. Infections with Rickettsia rickettsii (Rocky Mountain Spotted Fever) continue with severe consequences in South and Central America. The resurgence of R. conorii (Mediterranean Spotted Fever) in Europe, the Middle East and Africa, as well as a recent worldwide rise in murine typhus (R. typhi), highlights the threats of rickettsial diseases. Despite the public health importance of pathogenic Rickettsia spp.,, our limited knowledge of ricketsial biology has been an impediment to progress towards more effective intervention modalities. Our phylogenomics analyses have highlighted considerable variation across Rickettsia genomes, providing a framework to link particular genotypes with their associated disease phenotypes. For several bona fide secretory proteins that have been characterized in universal rickettsial processes (i.e., host cell adhesion, invasion and intracellular growth and survival), a patchy genomic distribution indicates that the mechanisms underpinning these processes are inherently different across rickettsial groups. For instance, our recent work on R. typhi (Typhus Group) identified a novel invasin, RalF, which interacts with host Arf6 in a process dependent on host phosphoinositide PIP2. Curiously, RalF genes are absent from species of Spotted Fever Group (SFG). Conversely, two well-characterized surface proteins (Sca0 and Sca2) of SFG pathogens are either absent (Sca0) or highly divergent (Sca2) in non-SFG rickettsial species. Thus, mechanisms of Rickettsia host cell invasion are more complex than previously appreciated, necessitating the need to employ a comparative approach for investigating the factors underpinning pathogenesis. Under this proposal, our work will focus on identifying the mammalian and invertebrate host cell targets of Sca3 and divergent Sca2 (d-Sca2) proteins from non-SFG species (Aim 1). Additionally, we will investigate the manner by which non- SFG species trigger phosphoinositide (PIP) metabolism to facilitate membrane ruffling and rickettsial endocytosis, with identified host proteins and PIPs present on the early endosome further explored as docking sites for rickettsial phospholipases that mediate phagosome escape (Aim 2). The successful outcome of this work will provide important clues on how divergent Rickettsia species utilize different molecules to achieve the universal rickettsial process of host cytoplasmic infection via induction of phagocytosis. We anticipate this knowledge to yield disease-specific therapeutic approaches to combat fatal rickettsioses.