Rickettsia-host interface and multiple paths to invasion

立克次体感染的全球影响表现为， 病原体，以及新认识的病原体的出现。的感染 立克次氏体（落基山斑疹热）继续造成严重后果， 南美洲和中美洲。R. Conorii（地中海斑疹热）， 欧洲、中东和非洲，以及最近世界范围内鼠斑疹伤寒的上升（R。 伤寒），突出了立克次体疾病的威胁。尽管公共卫生的重要性， 致病性立克次体属，，我们对立克次体生物学的有限知识 阻碍在更有效的干预模式方面取得进展。我们的基因组学 分析强调了立克次体基因组之间的相当大的差异， 将特定基因型与其相关疾病表型联系起来的框架。了几 在普遍立克次体过程中具有特征的真正分泌蛋白 (i.e.,宿主细胞粘附、侵袭和细胞内生长和存活），一种斑片状的基因组 分布表明，支撑这些过程的机制是内在的， 不同立克次体群体之间的差异。例如，我们最近在R.伤寒（斑疹伤寒组） 鉴定了一种新的侵袭素RalF，其在依赖于宿主的过程中与宿主Arf 6相互作用 磷酸肌醇PIP2。奇怪的是，RalF基因在斑点热病毒中并不存在， 组（SFG）。相反，SFG的两种充分表征的表面蛋白（Sca 0和Sca 2） 病原体在非SFG立克次体物种中不存在（Sca 0）或高度分化（Sca 2）。 因此，立克次体侵入宿主细胞的机制比以前更加复杂 因此，有必要采用比较的方法来调查 致病因素根据这项建议，我们的工作将集中在确定 Sca 3和趋异Sca 2（d-Sca 2）蛋白的哺乳动物和无脊椎动物宿主细胞靶标 非SFG物种（目标1）。此外，我们将调查非- SFG物质触发磷酸肌醇（PIP）代谢以促进膜褶皱和膜粘附。 立克次体的内吞作用，在早期内体上存在鉴定的宿主蛋白和PIP 进一步探索作为介导吞噬体的立克次体磷脂酶的停靠位点 逃脱（目标2）。这项工作的成功结果将提供重要的线索， 不同的立克次体物种利用不同的分子来实现通用立克次体 通过吞噬作用诱导宿主细胞质感染的过程。我们预料到这一点 知识，以产生针对疾病的治疗方法，以打击致命的立克次体病。

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.