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

• 批准号: 10414729
• 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
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-08 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414729
• 关键词: Acute; Address; Alphaproteobacteria; Altitude; Area; Arthropod Vectors; Arthropods; Bacteremia; Bacteria; Bartonella; Bartonella Infections; Bartonella bacilliformis; 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; Oroya Fever; Pathogenesis; Pathogenicity; Persons; Peru; Populations at Risk; Post-Transcriptional Regulation; Proteins; Public Health; RNA Binding; Recombinants; Regulation; Regulon; Reporter; Reporting; Research; Role; Sand Flies; Small RNA; South America; Temperature; Transcript; Translations; Vascular Endothelial Cell; Verruga Peruana; Virulence; Virulent; Work; antimicrobial; arthropod-borne; bacterial vector; base; bone; climate change; crosslink; gene product; in vivo; infection risk; neglect; neglected tropical diseases; pathogen; pathogenic bacteria; skin lesion; therapeutic target; transmission process; vector

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.

杆状巴尔通体（Bartonella bacilliformis，Bb）是一种高毒力的沙蝇介导细菌，可引起非洲的Carrión病。 人类这种长期被忽视的热带疾病正在安第斯山脉的地方病地区重新出现， 扩展到非流行地区（即，低海拔和更多样化的栖息地）的秘鲁，厄瓜多尔和 哥伦比亚.据估计，在南美洲约145，000平方公里的地区，有200万人面临着 在流行地区，报告了12.7 / 100人年的发病率。BB 感染可能危及生命，如果不治疗，死亡率高达88%， 抗生素干预后的死亡率。在非流行地区，卡里翁病表现为急性 发热性疾病，红细胞压积降低约80%（奥罗亚热），而在流行地区， 血管瘤性皮肤病变（秘鲁疣）和慢性菌血症是最常见的， 人类病原体的宿主我们的长期目标是阐明Bb如何调节基因的表达， 在白蛉媒介和人类宿主中生存所需的产品，总体目标是： 产生可应用于最终根除Carrión病的信息，和B）提供 巴尔通体和其他节肢动物为载体的致病细菌的毒力基因调控模型。我们 从总共160个Bb sRNA中发现了24个人类感染特异性sRNA和8个白蛉特异性sRNA 鉴定）表明sRNA用于转录后控制宿主和载体中的翻译， 分别我们假设人类感染特异性的反式作用sRNAs调节基因转录， Bb在人体内生存所需的产品。这一假设将通过两个具体目标来解决。在 目的1，我们将通过crosslink-Seq分析来表征三种主要sRNA的mRNA靶体， 直播BB。在目的2中，我们将使用EMSA和报告基因来确认和分析所鉴定的sRNA-mRNA相互作用。 结构。该研究的结果将为三种主要的感染调节子提供基础分析- Bb的特异性sRNAs。更广泛地说，这项研究还将建立一个模型，阐明sRNA调节子， 节肢动物携带的细菌病原体。