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Novel Bacterial Small RNAs as Determinants of Rickettsial Virulence and Transmission

新型细菌小 RNA 作为立克次体毒力和传播的决定因素

基本信息

批准号：
10170223
负责人：
Hema Prasad Narra
金额：
$ 54.09万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-13 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170223
关键词：
Aminoglycosides Anti-Bacterial Agents Antibiotics Arbovirus Infections Arthropod Vectors Arthropods Bacteria Bacterial Infections Biological Blood Substitutes Cataloging Catalogs Cells Code Complex Cytosol Development Disease Drug Targeting Endothelial Cells Endothelium Environment Epidemic Etiology Fleas Foundations Functional disorder Gene Expression Genes Genetic Genetic Transcription Goals Gram-Negative Bacteria Growth Human In Vitro Infection Injections Intervention Intravenous Investigation Knowledge Life Cycle Stages Life Style Link Maintenance Mammals Mediating Messenger RNA Metabolism Modality Morbidity - disease rate Mus Nature Needles Nutrient Organ Pathogenesis Pathogenicity Phagosomes Phase Physiological Publishing RNA Regulation Ribosomal RNA Rickettsia Rickettsia Infections Rickettsia conorii Rickettsia prowazekii Rickettsia rickettsii Rickettsia typhi Rocky Mountain Spotted Fever Role Scourge Small RNA Structure Syndrome Therapeutic Ticks Tissues Transcript Triad Acrylic Resin Tropism Typhus Untranslated RNA Vascular Diseases Vasculitis Vertical Disease Transmission Virulence War antimicrobial base biological adaptation to stress differential expression environmental change feeding human disease improved in vivo in vivo Model insight mortality mouse model mutant next generation novel obligate intracellular parasite pathogen pathogenic bacteria selective expression spotted fever tmRNA transcriptome transcriptome sequencing transcriptomics transmission process vascular inflammation vector vector tick vector transmission vector-borne infection virtual

项目摘要

Project Summary/Abstract Pathogenic Rickettsia species include Gram-negative bacteria known to cause human infections, namely spotted fever (R. rickettsii and R. conorii) and typhus (R. prowazekii and R. typhi), with serious morbidity and mortality. Tropism for microvascular endothelium, rapid escape from the phagosome, and growth/replication in the nutrient-rich cytosol as obligate intracellular parasites leading to vascular inflammation and dysfunction/damage constitute the salient features of rickettsial pathogenesis. Rickettsioses are vector-borne infections transmitted in nature by infected arthropods, including ticks and fleas. Rickettsiae are capable of circulating in their natural vectors through transstadial (horizontal) and transovarial (vertical) transmission and undergo dramatic niche-specific transcriptomic adaptations during their life-cycle to adjust to diverse environments in arthropod vectors and mammalian hosts. In this context, a major vacuity in our existing knowledge is the lack of understanding of regulatory mechanisms supporting their adaptive and/or pathogenic abilities in different host niches. Although small non-coding RNAs (sRNAs) are now firmly established as universal features of pathogenic bacteria and major regulators of their transcriptomes, the discovery and functional characterization of rickettsial sRNAs remained ignored until recently. We have now established and published that sRNAs in Rickettsia species are not only plentiful and functional (based on the identification of RC0877 and cydA as the respective target genes for novel R. conorii sRNAs Rc_sR35 and Rc_sR42, but are also differentially expressed in human versus tick host cells and in target organs in a mouse model of endothelial-target rickettsiosis akin to human disease. These findings serve as the foundation for a novel paradigm and genesis of our hypothesis that pathogenic rickettsiae exploit a network of sRNAs to adapt to host-specific environments (vectors vis-á-vis mammals) via modulation of gene expression. Having established the presence of sRNAs in both major groups of pathogenic rickettsiae, we now propose to conduct a comprehensive `compare and contrast' analysis of sRNA repertoire of R. conorii and R. typhi and their target genes during infection of human and mouse microvascular endothelium and to perform mechanistic and functional characterization of critically important rickettsial sRNAs [Aim 1]. We will next investigate their roles in rickettsial maintenance in natural vectors and vector-to-host transmission [Aim 2] and as potential determinants of virulence in the target organs of established murine models of R. conorii and R. typhi infection closely recapitulating the pathophysiology of human rickettsioses [Aim 3] . At conclusion, the proposed scientific enquiry will have a sustained positive impact through cataloging of novel rickettsial sRNAs and determination of mechanistic and functional insights into transcriptome regulation during distinct life-cycle phases of maintenance, pathogenesis, and transmission. The knowledge thus acquired will provide a platform for strategic development of new and improved treatment modalities against human rickettsial diseases.

项目摘要/摘要致病立克次体包括已知可引起人类感染的革兰氏阴性细菌，即斑点热(立克次体和康氏立克次体)和斑疹伤寒(普氏立克次体和斑疹伤寒)，发病率和死亡率。微血管内皮细胞的趋向性，快速逃离吞噬小体，以及生长/复制营养丰富的胞浆作为专性细胞内寄生虫导致血管炎症和功能障碍/损伤是立克次体发病的显著特征。立克次体是通过媒介传播的自然界中由受感染的节肢动物传播的感染，包括扁虱和跳蚤。立克次体能够通过经腹(水平)和经卵母细胞(垂直)传播在其自然载体中循环在它们的生命周期中经历戏剧性的利基特定的转录适应，以适应多样化节肢动物病媒和哺乳动物宿主的环境。在这种情况下，我们现有的一个主要真空知识是缺乏对支持其适应性和/或致病性的调节机制的了解在不同的宿主利基中的能力。尽管小的非编码RNA(SRNA)现在被牢固地建立为病原菌的普遍特征及其转录本的主要调节因子，这一发现和直到最近，立克次体sRNA的功能特性一直被忽视。我们现在已经建立了已发表的研究表明，立克次体中的sRNA不仅数量丰富，而且具有功能(基于对 RC0877和cydA分别是康氏杆菌新的sRNAs rc_sr35和rc_sR42的靶基因，但也在人与扁虱宿主细胞和小鼠模型的靶器官中差异表达内皮靶标立克次体病类似于人类疾病。这些发现是一部小说的基础我们假设致病立克次体利用sRNA网络来适应的范例和起源宿主特有的环境(载体与哺乳动物)通过基因表达的调节。已经确立了在这两个主要致病立克次体中存在sRNA，我们现在建议进行一项鸡伤寒沙门氏菌和伤寒沙门氏菌sRNA谱系及其靶标的综合“对比”分析基因在人和小鼠微血管内皮细胞感染中的作用关键的立克次体sRNA的功能特征[目标1]。接下来，我们将调查他们在自然媒介中立克次体的维持和媒介向宿主的传播 [目标2] 作为潜在的决定因素康氏杆菌和伤寒杆菌近距离感染小鼠模型的靶器官毒力研究概述人类立克次体病的病理生理学 [目标3] 。最后，提出的科学建议查询将通过编目新的立克次体sRNA和决心产生持续的积极影响在不同的生命周期阶段对转录组调控的机制和功能的洞察维持、发病和传播。这样获得的知识将提供一个平台，针对人类立克次体疾病制定新的和改进的治疗模式的战略。