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)：莱姆病伯氏疏螺旋体免疫逃避和持续感染的一个关键机制是VlsE表面蛋白的抗原变异。尽管细菌表面存在大量额外的蛋白质，但VlsE是唯一呈现其表面表位不断变化的抗原。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，它允许非VlsE表面抗原逃避宿主抗体的杀伤作用。尽管最近有这些证据，但VlsE在调节宿主免疫系统中的作用迄今从未被探索过。此外，关于VlsE抗原变异在病原体流行周期中的重要性的研究还不存在。我们的长期目标是确定VlsE对宿主免疫反应的任何潜在的调节作用。这项应用的目的是确定伯氏杆菌表面抗原是否需要VlsE和宿主免疫分子才能逃避宿主水库中的免疫监视。根据初步发现，我们的中心假设是VlsE通过需要IgM的过程来介导BBF01脂蛋白从宿主抗体中的免疫逃逸。这项研究的基本原理是，确定伯氏杆菌中VlsE启动的保护系统的存在和分子细节将极大地促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使命中与发展基础知识相关的部分相关，这可能有助于减轻人类疾病和残疾的负担。在初步研究结果的指导下，我们的假设将通过追求三个具体目标来检验：1)证明在自然宿主再次感染期间，伯氏杆菌表面抗原免疫回避的VlsE要求；2)确定BBF01逃避宿主抗体的VlsE要求；以及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-naive Permyscus小鼠将被壁虱来源的突变体或野生型疏螺旋体挑战，以寻找宿主重新感染的能力。在第二个目标下，用BBF01抗血清免疫的小鼠将被壁虱来源的野生型或VlsE/BBF01缺陷克隆攻击，以确定VlsE的存在是否阻止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，以检测VlsE介导的抗体逃避所需的IgM。这项拟议的工作是创新的，因为它涉及对伯氏杆菌具有积极体液反应的水库小鼠的再感染，以解决VlsE促进的保护问题，并利用各种VlsE突变伯氏杆菌克隆来感染蜱介体和宿主水库。 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。