Defining Microbial and Host Factors in Innate Immune Responses in Lyme Arthritis

莱姆关节炎先天免疫反应中的微生物和宿主因素的定义

基本信息

批准号：
8546266
负责人：
Klemen Strle
金额：
$ 13.26万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-17 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8546266
关键词：
Accounting Affect Agonist Amino Acids Anti-Inflammatory Agents Anti-inflammatory Antibiotic Therapy Antibiotics Arthritis Autoimmune Process Autoimmunity Biological Assay Biological Models Borrelia burgdorferi CXCL10 gene CXCL9 gene Candidate Disease Gene Caucasians Caucasoid Race Cell Culture System Cell surface Chronic Development Disease Epidemic Equilibrium European Event Frequencies Genes Genetic Genetic Polymorphism Genotype Guanine Human Immune Immune response Immune system Immunity Infection Infectious Agent Inflammatory Inflammatory Response Integration Host Factors Isoleucine Joints Lead Lesion Location Lyme Arthritis Lyme Disease Macrophage Activation Measures Modeling Molecular Oral Order Spirochaetales OspC protein Pathogenesis Pathway interactions Patients Play Population Positioning Attribute Production RNA Interference Reagent Refractory Rheumatism Rheumatoid Arthritis Role Serine Shapes Signal Transduction Single Nucleotide Polymorphism Staging Stream Syndrome System TLR2 gene Thymidine Ticks Toll-Like Receptor 1 Toxin Transmembrane Domain Virulence base cell type chemokine clinically relevant cytokine genome-wide insight killings macrophage microbial host novel pathogen public health relevance receptor response tick borne spirochete transmission process

项目摘要

DESCRIPTION (provided by applicant): Lyme disease has reached epidemic proportions and continues to spread in certain locations in the northeastern U.S. This region is affected by an especially inflammatory B. burgdorferi genotype, RST1 (OspC Type A) which has been shown to have a high transmission frequency among ticks, and may be primarily responsible for the emergence of Lyme disease in epidemic form in the northeastern U.S. in the late 20th century. However, B. burgdorferi spirochetes do not contain any known toxins that cause virulence. Rather, the disease that ensues following infection is related to the type of inflammatory immune responses that are stimulated by the spirochetes, and that are further augmented by a single nucleotide polymorphism in the TLR1 (1805GG) gene which is present in about half of the European Caucasians. To assess the role of these microbial and host factors in innate immune responses in Lyme arthritis we propose: 1. to compare cytokine and chemokine responses in macrophages, a single cell type, from normal donors with or without the 1805GG polymorphism, stimulated with a highly inflammatory RST1 (OspC type A) strain or a less inflammatory RST2 (OspC type K) strain, using bead-based Luminex assays, 2. to identify the signal transduction networks used by macrophages to sense and respond to OspC type A or K strains and to assess how the 1805GG TLR1 polymorphism alters these networks, by measuring the activation of cellular genes using genome-wide microarrays, and 3. to discern the functional consequences of pathways identified by gene microarrays using RNA interference reagents to inhibit candidate genes by which the TLR1 1805GG polymorphism alters the inflammatory response in our macrophage culture system. Antibiotic-refractory Lyme arthritis may be, at least in part, a syndrome of inappropriate macrophage activation involving both microbial and host genetics. Macrophages are also implicated in the pathogenesis of other rheumatic diseases including RA in which the synovial lesions are similar to those in patients with antibiotic-refractory Lyme arthritis. Thus, it is likely that the targeted approach developed here, to delineate mechanisms underlying inappropriate macrophage activation in antibiotic-refractory Lyme arthritis, will be valuable in understanding how innate immune inflammatory responses may lead to development of autoimmunity in the joint in other inflammatory and rheumatic diseases, including RA.

描述（由申请人提供）：莱姆病已达到流行比例，并继续在美国东北部的某些位置传播，该地区受到特别炎症的B. burgdorferi基因型RST1（OSPC A）的影响tick虫之间的高传输频率可能主要导致20世纪后期美国东北部流行病形式出现莱姆病的出现。然而，B。burgdorferi螺旋体不包含任何引起毒力的已知毒素。相反，感染后随后发生的疾病与螺旋体刺激的炎症免疫反应的类型有关，并被TLR1（1805GG）基因中的单个核苷酸多态性进一步增强，这些核苷酸多态性存在于欧洲大约一半中高加索人。为了评估这些微生物和宿主因素在莱姆关节炎中先天免疫反应中的作用，我们提出：1。比较巨噬细胞中的细胞因子和趋化因子反应，一种单细胞类型，来自有或没有1805GG多态性的正常供体，高度刺激，使用基于珠的Luminex Assays，2。炎症RST1（OSPC A型）应变或较低的炎症RST2（OSPC K型K）菌株2。确定巨噬细胞使用的信号转导网络，以感知和对OSPC型A或K型型或K型菌株和响应为了评估1805GG TLR1多态性如何通过使用全基因组微阵列测量细胞基因的激活来改变这些网络，而3。以识别基因微阵列使用RNA干扰试剂抑制TLR1的候选基因的途径的功能后果。 1805GG多态性改变了我们巨噬细胞培养系统中的炎症反应。抗生素难治性莱姆关节炎至少部分是一种涉及微生物和宿主遗传学的不适当巨噬细胞激活的综合征。巨噬细胞还与其他风湿性疾病的发病机理有关，包括RA，其中滑膜病变与抗生素难治性莱姆关节炎患者相似。因此，此处开发的有针对性方法很可能是为了描述抗生素杀伤性莱姆关节炎中不适当的巨噬细胞激活的机制，对于了解先天性免疫炎症反应可能会导致其他炎症和风湿性自身免疫性的发展，这将是有价值的。包括RA在内的疾病。