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，渗透症的免疫进化和持续感染的关键机制 Burgdorferi是VLSE表面蛋白的抗原变异。尽管存在大量 驻留在细菌表面上的其他蛋白质，VLSE是唯一表现出持续变化的抗原 它的表面表位。我们实验室的最新工作已经确定了VLSE介导的免疫驱逐系统 这允许非VLSE表面抗原逃脱宿主抗体的杀伤作用。尽管最近如此 迄今为止，从未探索过VLSE在调节宿主免疫系统中的作用。而且， 研究在病原体周期中VLSE抗原变异的重要性的研究是 不存在。我们的长期目标是确定VLSE对主机的任何潜在调节作用 免疫反应。本应用的目的是确定B. burgdorferi的逃脱 宿主储层中免疫监测的表面抗原需要VLSE和宿主免疫分子。 基于初步发现，我们的中心假设是VLSE介导BBF01的免疫进化 使用需要IgM的过程，来自储层宿主的抗体的脂蛋白。理由 拟议的研究是，确定VLSE促进保护系统的存在和分子细节 在B. burgdorferi中，将大大提高我们的知识，这种病原体如何用宿主免疫逃避 系统。这是拟议的研究与NIH使命的那部分有关的研究与发展有关 基本知识将有可能有助于减少人类疾病和残疾的伯恩斯。 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） 在重新感染期间，证明了B. burgdorferi表面抗原免疫的VLSE要求 天然水库主机； 2）确定BBF01从宿主抗体逃避的VLSE要求； 3） 确定VLSE介导的免疫逃避中IgM抗体的需求。在第一个目标下，vlse-na¿ peromyscus小鼠将挑战tick衍生的突变体或野生型疏螺旋体，以寻找能力 用于重新感染宿主。在第二个目标下，用BBF01抗血清免疫的小鼠将受到挑战 tick衍生的野生型或VLSE/BBF01缺陷克隆以确定VLSE的存在是否阻止BBF01 从宿主抗体识别。最后，第三个目标将利用抹布 - / - 小鼠感染了任何一种 突变体或野生型疏螺旋体为了主张VLSE介导的抗体演化的IgM需求。这 拟议的工作具有创新性，因为它涉及通过积极的体液反应重新感染储层小鼠 向B. burgdorferi进行，以解决VLSE启动保护的问题，并利用各种VLSE突变体 B. Burgdorferi克隆，用于感染tick矢量和宿主水库。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。