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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：
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
项目类别：
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

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.

项目总结/文摘