Targetomes of infection-specific small RNAs of Bartonella bacilliformis

杆状巴尔通体感染特异性小RNA的靶标组

基本信息

批准号：
10606530
负责人：
Michael F Minnick
金额：
$ 7.4万
依托单位：
UNIVERSITY OF MONTANA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-08 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606530
关键词：
Acclimatization Acute Address Alphaproteobacteria Altitude Area Arthropod Vectors Arthropods Bacteremia Bacteria Bartonella Bartonella Infections Bartonella bacilliformis Binding Biological Models Biology Cells Chronic Colombia Country Disease Outbreaks EMSA Ecuador Erythrocytes Fatality rate Fever Foundations Future Gene Expression Gene Expression Regulation Goals Habitats Hematocrit procedure Human In Vitro Incidence Infection Intervention Left Life Lutzomyia genus Mediating Messenger RNA Modeling Nutrient availability Oroya Fever Pathogenesis Pathogenicity Persons Peru Phlebotominae Populations at Risk Post-Transcriptional Regulation Proteins Public Health Recombinants Regulation Regulon Reporter Reporting Research Role Sand Flies Small RNA South America Temperature Transcript Translations Vascular Endothelial Cell Verruga Peruana Virulent Work antimicrobial arthropod-borne bacterial vector bone climate change crosslink gene product in vivo infection risk neglect neglected tropical diseases pathogen pathogenic bacteria skin lesion therapeutic target transmission process vector virulence gene

Acclimatization Acute Address Alphaproteobacteria Altitude Area Arthropod Vectors Arthropods Bacteremia Bacteria Bartonella Bartonella Infections Bartonella bacilliformis Binding Biological Models Biology Cells Chronic Colombia Country Disease Outbreaks EMSA Ecuador Erythrocytes Fatality rate Fever Foundations Future Gene Expression Gene Expression Regulation Goals Habitats Hematocrit procedure Human In Vitro Incidence Infection Intervention Left Life Lutzomyia genus Mediating Messenger RNA Modeling Nutrient availability Oroya Fever Pathogenesis Pathogenicity Persons Peru Phlebotominae Populations at Risk Post-Transcriptional Regulation Proteins Public Health Recombinants Regulation Regulon Reporter Reporting Research Role Sand Flies Small RNA South America Temperature Transcript Translations Vascular Endothelial Cell Verruga Peruana Virulent Work antimicrobial arthropod-borne bacterial vector bone climate change crosslink gene product in vivo infection risk neglect neglected tropical diseases pathogen pathogenic bacteria skin lesion therapeutic target transmission process vector virulence gene

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项目摘要

Bartonella bacilliformis (Bb) is a highly-virulent, sand fly-vectored bacterium responsible for Carrión’s disease in humans. This chronically-neglected tropical disease is re-emerging in endemic regions of the Andes and expanding into non-endemic areas (i.e., lower altitudes and more diverse habitats) of Peru, Ecuador and Colombia. An estimated two million people in an area of ~145,000 square-km in South America are at risk of infection by Bb, and incidence rates of 12.7 / 100 person-years have been reported in endemic regions. Bb infections are potentially life-threatening, with fatality rates as high as 88% if left untreated, and ~10% fatality rates following antimicrobial intervention. In non-endemic regions, Carrión’s disease manifests as an acute febrile illness with an ~80% reduction in erythrocyte hematocrit (Oroya fever), whereas in endemic regions, angiomatous skin lesions (verruga peruana) and chronic bacteremia are most common, effectively creating a human reservoir for the pathogen. Our long-term goal is to elucidate how Bb regulates expression of gene products required to survive in the sand fly vector and human host, with overarching objectives of: a) generating information that can be applied to the eventual eradication of Carrión's disease and b) providing a model of virulence gene regulation in Bartonella and other arthropod-vectored, pathogenic bacteria. Our discovery of 24 human-infection-specific sRNAs and 8 sand fly-specific sRNAs (from a total of 160 Bb sRNAs identified) suggests that sRNAs are used to post-transcriptionally control translation in the host and vector, respectively. We hypothesize that human-infection-specific, trans-acting sRNAs regulate transcripts for gene products that are required for Bb survival in humans. The hypothesis will be addressed by two specific aims. In aim 1, we will characterize the mRNA targetomes of three prominent sRNAs through crosslink-Seq analysis of live Bb. In aim 2, we will confirm and analyze the identified sRNA-mRNA interactions using EMSAs and reporter constructs. Results of the study will provide a foundational analysis of the regulons for three dominant, infection- specific sRNAs of Bb. More broadly, the research will also establish a model for elucidating sRNA regulons in arthropod-vectored bacterial pathogens.

Bartonella bacilliformis（BB）是一种高度病毒，由沙蝇的细菌负责Carrión的疾病人类。这种慢性化的热带疾病正在安第斯山脉的地方性地区重新出现扩展到秘鲁，厄瓜多尔和哥伦比亚。估计在南美约有200万平方公里的地区有200万人 BB感染了内在地区的BB感染，并且已有12.7 / 100人年的事件。 BB 感染潜在威胁生命，如果未治疗，死亡率高达88％，死亡〜10％抗菌干预后的速率。在非目标地区，Carrión的疾病表现为急性红细胞血细胞比容降低约80％的发热疾病（Oroya Fever），而在内在地区，血管瘤皮肤病变（Verruga Peruana）和慢性细菌最常见，有效地产生了病原体的人类储层。我们的长期目标是阐明BB如何调节基因的表达在沙子矢量和人类宿主中生存所需的产品，具有：a）的总体物体生成可用于最终消除Carrión病的信息，b）提供 Bartonella和其他节肢动物载体的致病细菌中病毒基因调节的模型。我们的发现24个人类感染特异性SRNA和8个沙蝇特异性SRNA（总共160 BB SRNA 已确定的）建议SRNA用于在主机和向量中进行转录后控制翻译，分别。我们假设人类感染特异性的反式sRNA调节基因的转录本 BB生存所需的产品。该假设将由两个具体目标解决。在 AIM 1，我们将通过对三个突出的SRNA的mRNA靶标，通过交联的分析分析现场BB。在AIM 2中，我们将使用EMSAS和Reporter确认并分析已识别的SRNA-MRNA相互作用构造。该研究的结果将对三种主要感染的法规提供基础分析。 BB的特定SRNA。更广泛地，该研究还将建立一个阐明SRNA法规的模型节肢动物矢量的细菌病原体。