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.

项目概要 莱姆病螺旋体疏螺旋体免疫逃避和持续感染的关键机制 尽管存在大量的伯氏疏螺旋体，但它是 VlsE 表面蛋白的抗原变异。 由于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 我们实验室最近的工作发现了一个可能的 VlsE 介导的免疫逃避系统。 尽管最近出现了这种情况，但它仍允许非 VlsE 表面抗原逃避宿主抗体的杀伤作用。 证据表明，迄今为止，VlsE 在调节宿主免疫系统中的作用尚未被探索过。 调查vlsE抗原变异在病原体地方性动物流行周期中的重要性的研究有 我们的长期目标是确定 VlsE 对宿主的任何潜在调节作用。 该应用的目的是确定伯氏疏螺旋体是否逃逸。 来自宿主储存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 BBF01 的免疫逃避 使用需要 IgM 的过程从宿主储存库的抗体中提取脂蛋白。 拟议的研究是确定 VlsE 促进的保护系统的存在和分子细节 伯氏疏螺旋体中的细菌将显着提高我们对这种病原体如何逃避宿主免疫的了解 因此，拟议的研究与 NIH 的使命中涉及开发的部分相关。 可能有助于减轻人类疾病和残疾负担的基础知识。 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) 证明在再次感染伯氏疏螺旋体期间避免伯氏疏螺旋体表面抗原免疫的 VlsE 要求 天然储存宿主；2) 确定 BBF01 逃避宿主抗体的 VlsE 要求；3) 确定 VlsE 介导的免疫逃避中对 IgM 抗体的要求 在第一个目标下，VlsE-na¿维 Peromyscus 小鼠将接受蜱源突变体或野生型疏螺旋体的挑战，以寻找能力 在第二个目标下，用 BBF01 抗血清免疫的小鼠将受到任一挑战。 蜱衍生的野生型或 VlsE/BBF01 缺陷克隆，以确定 VlsE 的存在是否会阻止 BBF01 最后，第三个目标将利用感染了任一病毒的 Rag-/- 小鼠。 突变型或野生型疏螺旋体，以测定 VlsE 介导的抗体逃避的 IgM 需求。 拟议的工作具有创新性，因为它涉及具有活跃体液反应的储存小鼠的再感染 伯氏疏螺旋体以解决 VlsE 促进的保护问题，并利用各种 vlsE 突变体 这种方法可能会提供用于感染蜱载体和宿主宿主的伯氏疏螺旋体克隆。 在制定预防和治疗人类莱姆病的策略方面提供更多有用的知识。