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: 10372391
• 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 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372391
• 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; Lead; Leukocytes; Lyme Disease; Medical Care Costs; Modeling; Mouse Strains; Mutation; Nervous system structure; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phagocytosis Induction; 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; 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.

项目摘要/摘要 莱姆病是由tick传播病原体伯氏伯氏菌感染引起的，可能导致 影响关节，心脏和神经系统的炎症病理。因为没有疫苗或有效 媒介控制反对感染，莱姆病是并且将继续是重要的公共卫生 忧虑。该提案直接解决了NIH的tick虫疾病研究的战略计划，并与 了解理解基本生物学的特定应用以及与宿主的互动 tick骨病原体。这些研究的总体目标是确定候选人B. burgdorferi目标 莱姆病的预防和治疗治疗。 B. burgdorferi的分离株显示高水平的遗传异质性，某些基因型与 人类发病机理增加。据报道，高致病性基因型诱导了更健壮的 宿主细胞的I型干扰素反应，阻塞I型干扰素消除了实验室的病理 莱姆病小鼠模型；强调莱姆发病机理中I型干扰素的重要性 疾病。 尽管干扰素信号在莱姆病的发病机理中很重要，但细菌因素 参与刺激干扰素的产生尚不清楚。最近，B的存在。 显示burgdorferi线性质粒LP36与I型和III型干扰素产生相关 细胞离体，但是涉及的特定基因以及哺乳动物感染期间的后果尚未 已确定。 我们假设LP36编码刺激产生所需的未识别的毒力决定因素 来自宿主细胞的干扰素，以及哺乳动物感染期间疾病病理的诱导。有选择地 在B. B. Burgdorferi中删除LP36的不同区域，我们将在我们的研究中解决以下目的：（1）定义 先天免疫细胞反应所需的LP36基因； （2）确定LP36基因对 哺乳动物感染期间的细菌定植和病理诱导。 我们对线性质粒截断的创新方法可以筛选大型质粒区域 新型毒力因子的存在。使用不同尺寸的系统截断，我们希望确定 LP36基因参与宿主细胞刺激干扰素产生的基因，并确定它们在 病原体适应性和感染过程中的组织病理学。这项工作将移动莱姆病研究领域 前进，由于这些因素是用于新的预防性和治疗方法的理想候选靶标。 Burgdorferi感染和相关的免疫病理学。