Characterizing the impact of small regulatory RNAs on the virulence of Brucella spp.

表征小调节 RNA 对布鲁氏菌属毒力的影响。

• 批准号: 10057427
• 负责人: Clayton C Caswell
• 金额: $ 19.57万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057427
• 关键词: Adopted; Animals; Antibiotic Therapy; Antibiotics; Bacteria; Binding; Bioinformatics; Biological; Biological Process; Biology; Brucella; Brucella abortus; Brucellosis; Cells; Characteristics; Chronic; Critical Pathways; Data; Development; Disease; Domestic Animals; Event; Exposure to; Future; Gene Expression; Gene Expression Regulation; Genetic; Genetic Transcription; Glean; Goals; Human; Immune; In Vitro; Infection; Laboratories; Mediating; Mediator of activation protein; Messenger RNA; Methodology; Modeling; Molecular Chaperones; Mus; Nutrient; Oxidative Stress; Oxygen; Pathogenesis; Pathway interactions; Phenotype; Procedures; Process; Proteomics; RNA; Reactive Oxygen Species; Recurrent disease; Relapse; Research; Research Personnel; Role; Small RNA; Sterility; Stress; Structure; System; Testing; Therapeutic; Transcript; Treatment Protocols; Vaccines; Virulence; Wild Animals; Work; abortion; attenuation; bioweapon; combat; design; experimental study; exposed human population; flu; host colonization; macrophage; mouse model; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; novel vaccines; pathogen; programs; therapeutic development; transcriptomics; vaccine development

Project Summary Brucella spp. are bacteria that naturally infect a variety of domesticated and wild animals leading to abortions and sterility, and these bacteria are also capable of causing debilitating human infections, which often result from human exposure to infected animals and animal products. Brucella spp. are considered threats as potential biological weapons. Importantly, antibiotic treatment against brucellosis is prone to disease relapse, and there is currently no safe and effective vaccine to protect humans against infection with Brucella. The brucellae are intracellular pathogens that reside within immune cells called macrophages where they replicate in a specialized compartment, and the capacity of Brucella to survive and replicate within macrophages is essential to their ability to cause disease. Over the last few years, our laboratory has characterized genetic pathways that are critical for the intracellular survival and pathogenesis of Brucella strains, and specifically, we have identified small regulatory RNAs (sRNAs) that are essential for Brucella virulence. Preliminary experiments have revealed the presence of more than 20 novel sRNAs in B. abortus, and we have identified one of these sRNAs, called Bsr18 (for Brucella small RNA) that is required for the for virulence of B. abortus in a mouse model of chronic Brucella infection. We hypothesize that Bsr18 is produced under biologically relevant conditions, such as acidic pH, oxidative stress, nutrient limitation, and/or diminished oxygen, and moreover, we hypothesize that Bsr18 is required for the ability of B. abortus to cope with these conditions. Additionally, it is hypothesized that Bsr18 regulates the expression of genes important for the infectivity of B. abortus. Therefore, we plan to characterize the biological and regulatory functions of Bsr18, and in the end, the information gleaned from these studies may be used to develop new therapeutic and vaccine strategies against human Brucella infection.

项目摘要 布鲁氏菌是自然感染各种驯养和野生动物的细菌， 流产和不育，这些细菌也能引起使人衰弱的感染， 通常是由于人类接触受感染的动物和动物产品而引起的。布鲁氏菌被认为 潜在的生物武器威胁。重要的是，针对布鲁氏菌病的抗生素治疗容易导致疾病 布鲁氏菌是一种易复发的疾病，目前还没有安全有效的疫苗来保护人类免受布鲁氏菌感染。 布鲁氏菌是细胞内病原体，存在于称为巨噬细胞的免疫细胞内， 在一个专门的隔间中复制，布鲁氏菌的生存和复制能力 巨噬细胞对它们致病的能力至关重要。在过去的几年里，我们的实验室 表征了对布鲁氏菌细胞内存活和发病至关重要的遗传途径 菌株，特别是，我们已经确定了小调控RNA（sRNAs）是必不可少的布鲁氏菌 毒性 初步实验已经揭示了B中存在超过20种新的sRNA。流产，我们 我已经鉴定出一种称为Bsr 18（布鲁氏菌小RNA）的sRNA，它是布鲁氏菌毒力所必需的 的B。在慢性布鲁氏菌感染小鼠模型中的流产。我们假设Bsr 18是在 生物学相关条件，如酸性pH、氧化应激、营养限制和/或减少 此外，我们假设Bsr 18是B的能力所必需的。流产，以科普这些 条件此外，假设Bsr 18调节对免疫应答重要的基因的表达。 B的传染性。流产因此，我们计划表征Bsr 18的生物学和调节功能， 最后，从这些研究中收集到的信息可以用于开发新的治疗方法和疫苗。 预防人类布鲁氏菌感染的策略。