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: 9247117
• 负责人: Troy Michael Bankhead
• 金额: $ 25.47万
• 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/9247117
• 关键词: Address; Animals; Antibodies; Antibody Response; Antigenic Variation; Antigens; Area; Arthritis; Biological Assay; Borrelia; Borrelia Infections; Borrelia burgdorferi; Carditis; Data; Epitopes; Exhibits; Goals; Health; Human; Immune; Immune Evasion; Immune Sera; Immune response; Immune system; Immunize; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunologic Factors; Immunologic Surveillance; Infection; Knowledge; Life Cycle Stages; Lipoproteins; Lyme Disease; Lyme Infection; 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; United States National Institutes of Health; Variant; Work; base; disability; enzootic; experimental study; immunogenic; innovation; killings; mutant; pathogen; prevent; public health relevance; response; surface coating; vector

DESCRIPTION (provided by applicant): 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-naive 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 i 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.

描述（由申请人提供）：莱姆病螺旋体伯氏疏螺旋体免疫逃避和持续感染的关键机制是 VlsE 表面蛋白的抗原变异。尽管细菌表面存在大量其他蛋白质，但 VlsE 是唯一表现出其表面表位持续变化的抗原。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，该系统允许非 VlsE 表面抗原逃避宿主抗体的杀伤作用。尽管有最近的证据，但迄今为止尚未探索过 VlsE 在调节宿主免疫系统中的作用。此外，尚不存在研究vlsE抗原变异在病原体地方性流行周期中的重要性的研究。我们的长期目标是确定 VlsE 对宿主免疫反应的任何潜在调节作用。本应用的目的是确定伯氏疏螺旋体表面抗原从宿主储存库中的免疫监视中逃脱是否需要 VlsE 和宿主免疫分子。根据初步发现，我们的中心假设是 VlsE 通过需要 IgM 的过程介导 BBF01 脂蛋白从储存宿主的抗体中进行免疫逃避。这项研究的基本原理是，鉴定伯氏疏螺旋体中 VlsE 促进的保护系统的存在和分子细节将显着增进我们对这种病原体如何逃避宿主免疫系统的了解。因此，拟议的研究与 NIH 使命的一部分相关，即发展基础知识，这将有可能有助于减轻人类疾病和残疾的负担。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进行检验：1）证明在自然储存宿主再感染期间伯氏疏螺旋体表面抗原免疫避免的 VlsE 要求； 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 抗体的需求。第一个目标是，VlsE 幼稚的 Peromyscus 小鼠将受到蜱源突变体或野生型疏螺旋体的挑战，以寻找宿主再感染的能力。在第二个目标下，用 BBF01 抗血清免疫的小鼠将受到蜱源野生型或 VlsE/BBF01 缺陷克隆的攻击，以确定 VlsE 的存在是否会阻止 BBF01 被宿主抗体识别。最后，第三个目标将利用感染突变型或野生型疏螺旋体 i 的 Rag-/- 小鼠来测定 VlsE 介导的抗体逃避的 IgM 需求。这项工作具有创新性，因为它涉及对伯氏疏螺旋体产生活跃体液反应的储存小鼠进行再感染，以解决 VlsE 促进的保护问题，并利用各种 vlsE 突变体伯氏疏螺旋体克隆来感染蜱载体和宿主储存库。 这种方法可能会为制定预防和治疗人类莱姆病的策略提供更多有用的知识。