Study of Immune Avoidance During the Enzootic Cycle of the Lyme Disease Pathogen

莱姆病病原体地方性流行周期中免疫回避的研究

• 批准号: 8611524
• 负责人: Troy Michael Bankhead
• 金额: $ 24.9万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8611524
• 关键词: Address; Animals; Antibodies; Antibody Formation; Antigenic Variation; Antigens; Area; Arthritis; Biological Assay; Borrelia; Borrelia burgdorferi; Carditis; Data; Epitopes; Exhibits; Goals; Health; Human; Immune; Immune Sera; Immune response; Immune system; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunologic Surveillance; Infection; Knowledge; Life Cycle Stages; Lipoproteins; Lyme Disease; Masks; Mediating; Membrane Proteins; Mission; Molecular; Mus; Neurologic; North America; Organism; Pathogenesis; Peromyscus; Process; Proteins; Public Health; Research; Role; SCID Mice; Specificity; Surface; Surface Antigens; System; T-Lymphocyte; Testing; Tick-Borne Diseases; Ticks; Trypanosoma brucei brucei; Variant; Work; base; disability; enzootic; immunogenic; innovation; killings; mutant; pathogen; prevent; public health relevance; research study; response; surface coating; vector

Project Summary A key mechanism for immune evasion and persistent infection by the Lyme disease spirochete, Borrelia burgdorferi, is antigenic variation of the VlsE surface protein. Despite the presence of a substantial number of additional proteins residing on the bacterial surface, VlsE is the only antigen that exhibits ongoing variation of its surface epitope. Recent work in our lab has identified a possible VlsE-mediated immune evasion system that allows non-VlsE surface antigens to escape the killing effects of host antibodies. Despite this recent evidence, a role for VlsE in modulating the host immune system has never been explored to date. Moreover, studies investigating the importance of vlsE antigenic variation during the pathogen's enzootic cycle are nonexistent. Our long-term goals are to determine any potential modulatory effects by VlsE on the host immune response. The objective of this application is to determine whether the escape of B. burgdorferi surface antigens from immune surveillance in the host reservoir requires VlsE and host immune molecules. Based on preliminary findings, our central hypothesis is that VlsE mediates immune evasion of the BBF01 lipoprotein from antibodies of the reservoir host using a process that requires IgM. The rationale for the proposed research is that identifying the presence and molecular details of a VlsE-promoted protection system in B. burgdorferi would significantly advance our knowledge how this pathogen evades with the host immune system. Thus, the proposed research is relevant to that part of NIH's mission that pertains to developing fundamental knowledge that will potentially help to reduce the burdens of human illness and disability. Guided by preliminary findings, our hypothesis will be tested by pursuing three specific aims: 1) Demonstrate a VlsE requirement for B. burgdorferi surface antigen immune avoidance during reinfection of the natural reservoir host; 2) Determine a VlsE requirement for BBF01 evasion from host antibodies; and 3) Determine a requirement for IgM antibodies in VlsE-mediated immune evasion. Under the first aim, VlsE-na¿ve Peromyscus mice will be challenged with either tick-derived mutant or wild type Borrelia to look for a capacity for host reinfection. Under the second aim, mice immunized with BBF01 antisera will be challenged with either tick-derived wild type or VlsE/BBF01-deficient clones to determine if the presence of VlsE prevents BBF01 from being recognized by host antibodies. Finally, the third aim will utilize Rag-/- mice infected with either mutant or wild type Borrelia in order to assay for an IgM requirement for VlsE-mediated antibody evasion. The proposed work is innovative, because it involves reinfection of reservoir mice with an active humoral response to B. burgdorferi in order to address the question of VlsE-promoted protection, and utilizes various vlsE mutant B. burgdorferi clones for infection of both the tick vector and host reservoir. This approach will likely provide more useful knowledge in developing strategies to prevent and treat Lyme disease in humans.

项目摘要 莱姆病螺旋体持续感染和免疫逃避的关键机制 Burgdorferi是VlsE表面蛋白的抗原性变异。尽管有相当数量的 存在于细菌表面的其他蛋白质，VlsE是唯一表现出持续变异的抗原 它的表面表位。我们实验室最近的工作发现了一种可能的VlsE介导的免疫逃避系统 这使得非VlsE表面抗原能够逃脱宿主抗体的杀伤作用。尽管最近出现了这种情况 有证据表明，VlsE在调节宿主免疫系统中的作用迄今从未被探索过。此外， 研究VlsE抗原变异在病原体流行周期中的重要性的研究是 根本不存在。我们的长期目标是确定VlsE对宿主的任何潜在调节作用 免疫反应。该应用程序的目的是确定伯氏杆菌的逃逸是否 宿主水库中免疫监视的表面抗原需要VlsE和宿主免疫分子。 根据初步发现，我们的中心假设是VlsE介导了BBF01的免疫逃避 使用需要IgM的过程从宿主抗体中提取脂蛋白。该计划的基本原理 建议的研究是确定VlsE促进的保护系统的存在和分子细节 在伯氏杆菌中，将大大提高我们对这种病原体如何通过宿主免疫逃避的了解 系统。因此，拟议的研究与NIH任务中与开发有关的部分相关 可能有助于减轻人类疾病和残疾负担的基本知识。 在初步发现的指导下，我们的假设将通过追求三个具体目标来检验：1) 证明了在伯氏杆菌再感染期间避免表面抗原免疫的VlsE要求 天然宿主；2)确定BBF01逃避宿主抗体的VlsE要求；以及3) 确定在VlsE介导的免疫逃避中对IgM抗体的需求。在第一个目标下，VlsE-NA？ve Permyscus小鼠将被扁虱来源的突变体或野生型疏螺旋体挑战，以寻找能力 用于宿主的再感染。在第二个目标下，用BBF01抗血清免疫的小鼠将被攻击 Tick来源的野生型或VlsE/BBF01缺陷克隆以确定VlsE的存在是否阻止BBF01 不会被宿主抗体识别。最后，第三个目标将利用感染了这两种病毒的RAG-/-小鼠 突变或野生型疏螺旋体，以检测VlsE介导的抗体逃避所需的IgM。这个 拟议的工作是创新的，因为它涉及到对具有积极体液反应的储藏鼠的再次感染 为了解决VlsE促进保护的问题，并利用各种VlsE突变体 伯氏杆菌克隆体可同时感染硬虱媒介和宿主宿主。这种方法可能会提供 在制定预防和治疗人类莱姆病的策略方面有更多有用的知识。