Identification of linear plasmid lp36-encoded virulence determinants in the Lyme disease spirochete Borrelia burgdorferi

莱姆病螺旋体伯氏疏螺旋体中线性质粒 lp36 编码的毒力决定簇的鉴定

• 批准号: 10514623
• 负责人: Timothy Casselli
• 金额: $ 7.05万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10514623
• 关键词: Address; Affect; Animal Model; Animals; Arthritis; Bacteria; Bacterial Adhesion; Bacterial Genes; Binding; Biology; Borrelia burgdorferi; Cells; Clinical; Coculture Techniques; Complement; Disease; Disease susceptibility; Etiology; Genes; Genetic; Genetic Heterogeneity; Genome; Genotype; Goals; Heart; Human; Immune; Immune response; Incidence; Infection; Inflammation Mediators; Inflammatory; Inflammatory Response; Interferon Type I; Interferons; Joints; Kinetics; Knowledge; Laboratory mice; Leukocytes; Lyme Disease; Medical Care Costs; Modeling; Mouse Strains; Mutation; Nervous System; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phagocytosis; Plasmids; Production; Public Health; Reporting; Research; Role; Severities; Signal Transduction; Strategic Planning; Therapeutic; Tick-Borne Diseases; Tissues; United States; United States National Institutes of Health; Up-Regulation; Vaccines; Virulence; Virulence Factors; Work; candidate identification; cell type; cytokine; experimental study; fitness; genomic locus; human model; immunopathology; innovation; lyme pathogenesis; mouse model; mutant; novel; pathogen; peripheral blood; prophylactic; response; screening; skin lesion; tick-borne pathogen; vector control; vector tick

PROJECT SUMMARY/ABSTRACT Lyme disease, which is caused by infection with the tick-borne pathogen Borrelia burgdorferi, can lead to inflammatory pathologies affecting the joints, heart, and nervous systems. As there are no vaccines or effective vector controls against the infection, Lyme disease is and will continue to be a significant public health concern. This proposal directly addresses the NIH Strategic Plan for Tickborne Disease Research, with specific applications towards understanding the fundamental biology of, and the host interactions with tickborne pathogens. The overall goal of these studies is to identify candidate B. burgdorferi targets for prophylactic and therapeutic treatments for Lyme disease. Isolates of B. burgdorferi display a high level of genetic heterogeneity, and certain genotypes correlate with increased pathogenesis in humans. High pathogenicity genotypes have been reported to induce a more robust Type I interferon response from host cells, and blocking Type I interferon abrogates pathology in laboratory mouse models of Lyme disease; underscoring the importance of Type I interferon in the pathogenesis of Lyme disease. Despite the importance of interferon signaling in the pathogenesis of Lyme disease, the bacterial factors involved in stimulating production of interferon are not well understood. Recently, the presence of the B. burgdorferi linear plasmid lp36 was shown to correlate with Type I and Type III interferon production from host cells ex vivo, however the specific genes involved and the consequences during mammalian infection have not been determined. We hypothesize that lp36 encodes unidentified virulence determinants required for stimulating production of interferon from host cells, as well as induction of disease pathology during mammalian infection. By selectively deleting different regions of lp36 in B. burgdorferi, we will address the following aims in our studies: (1) Define the lp36 genes required for innate immune cell responses; and (2) Determine the requirement of lp36 genes for bacterial colonization and induction of pathology during mammalian infection. Our innovative approach of linear plasmid truncation allows for screening large plasmid regions for the presence of novel virulence factors. Using systematic truncations of different sizes, we expect to identify the lp36 genes involved in stimulation of interferon production from host cells, and determine their roles in pathogen fitness and tissue pathology during infection. This work will move the field of Lyme disease research forward, as such factors are ideal candidate targets for novel prophylactic and therapeutic treatments for B. burgdorferi infection and associated immunopathologies.

项目总结/摘要 莱姆病是由蜱传病原体伯氏疏螺旋体感染引起的， 影响关节、心脏和神经系统的炎性病理。由于没有疫苗或有效的 莱姆病是并将继续是一个重大的公共卫生问题， 关心该提案直接针对NIH蜱传疾病研究战略计划， 对理解的基础生物学的具体应用，和主机相互作用与 蜱传病原体这些研究的总体目标是确定候选药物B。Burgdorferi目标 莱姆病的预防性和治疗性治疗。 B的分离株。burgdorferi显示出高水平的遗传异质性，某些基因型与 增加了人类的发病率。据报道，高致病性基因型可诱导更强的 I型干扰素从宿主细胞的反应，并阻断I型干扰素消除病理在实验室 莱姆病小鼠模型;强调I型干扰素在莱姆病发病机制中的重要性 疾病 尽管干扰素信号传导在莱姆病发病机制中的重要性，但细菌因素 参与刺激干扰素产生的机制尚不清楚。最近，B. 螺旋体线性质粒lp 36与宿主产生I型和III型干扰素相关 然而，涉及的特定基因和哺乳动物感染过程中的后果还没有 确定了 我们假设lp 36编码刺激产生 来自宿主细胞的干扰素，以及在哺乳动物感染期间诱导疾病病理。通过选择性 删除B中lp 36的不同区域。burgdorferi，我们将在我们的研究中解决以下目标：（1）定义 先天性免疫细胞应答所需的lp 36基因;和（2）确定lp 36基因对 细菌定植和哺乳动物感染过程中的病理诱导。 我们的线性质粒截短的创新方法允许筛选大的质粒区域， 存在新的毒力因子。使用不同大小的系统截断，我们期望识别 lp 36基因参与刺激宿主细胞产生干扰素，并决定它们在 病原体适合度和感染期间的组织病理学。这项工作将推动莱姆病研究领域 因此，这些因子是B的新型预防和治疗的理想候选靶点。 伯氏菌感染和相关的免疫病理学。