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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要莱姆病是由蜱传病原体伯氏疏螺旋体感染引起的，可导致影响关节、心脏和神经系统的炎症病理。由于没有疫苗或有效药物通过病媒控制感染，莱姆病现在并将继续成为重要的公共卫生问题忧虑。该提案直接涉及 NIH 蜱传疾病研究战略计划，其中理解其基本生物学以及宿主相互作用的具体应用蜱传病原体。这些研究的总体目标是确定伯氏疏螺旋体的候选目标莱姆病的预防和治疗。伯氏疏螺旋体分离株表现出高度的遗传异质性，某些基因型与增加人类发病机制。据报道，高致病性基因型可诱导更强大的来自宿主细胞的 I 型干扰素反应，并阻断 I 型干扰素消除实验室病理学莱姆病小鼠模型；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的发病机制中很重要，但细菌因素参与刺激干扰素产生的机制尚不清楚。最近，B. 伯氏疏螺旋体线性质粒 lp36 与宿主 I 型和 III 型干扰素的产生相关细胞离体，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已确定。我们假设 lp36 编码刺激产生所需的未知毒力决定簇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。通过选择性地删除伯氏疏螺旋体中lp36的不同区域，我们将在我们的研究中实现以下目标：（1）定义先天免疫细胞反应所需的 lp36 基因； (2) 确定 lp36 基因的需要哺乳动物感染期间细菌定植和病理诱导。我们的线性质粒截断创新方法可以筛选大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 lp36 基因参与刺激宿主细胞产生干扰素，并决定它们在感染期间的病原体适应性和组织病理学。这项工作将推动莱姆病研究领域展望未来，因为这些因素是新型芽孢杆菌预防和治疗方法的理想候选目标。伯氏杆菌感染和相关的免疫病理学。