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）：莱姆病螺旋体的免疫逃避和持续感染的关键机制，伯氏伯氏菌，是VLSE表面蛋白的抗原变异。尽管存在大量的其​​他蛋白质位于细菌表面上，但VLSE是唯一表现出其表面表位持续变化的抗原。我们实验室中的最新工作已经确定了VLSE介导的免疫逃避系统，该系统允许非VLSE表面抗原逃脱宿主抗体的杀戮作用。尽管最近有证据表明，VLSE在调节宿主免疫系统中的作用从未探索过。此外，研究在病原体enzootic循环中VLSE抗原变异的重要性的研究不存在。我们的长期目标是确定VLSE对宿主免疫反应的任何潜在调节作用。该应用的目的是确定伯格多菲尔菲表面抗原在宿主储层中免疫监测的逃脱是否需要VLSE和宿主免疫分子。基于初步发现，我们的中心假设是，VLSE使用需要IgM的过程介导了从储层宿主的抗体中对BBF01脂蛋白的免疫逃避。拟议的研究的理由是，确定B. burgdorferi中VLSE促进的保护系统的存在和分子细节将大大促进我们的知识如何使用宿主免疫系统逃避。因此，拟议的研究与NIH使命的那部分有关，该研究与发展基本知识有关，这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的来检验：1）在重新感染天然储层宿主期间，证明了对B. burgdorferi表面抗原免疫的VLSE要求； 2）确定BBF01从宿主抗体逃避的VLSE要求； 3）确定对VLSE介导的免疫逃避中IgM抗体的要求。在第一个目标下，vlse-nive peromyscus小鼠将受到tick虫突变体或野生型漏斗的挑战，以寻找宿主再感染的能力。在第二个目标下，用tick衍生的野生型或VLSE/BBF01缺陷的克隆来挑战以BBF01抗血清免疫的小鼠，以确定VLSE的存在是否阻止BBF01被宿主抗体识别。最后，第三个目标将利用抹布 - / - 小鼠感染了突变体或野生型漏洞I，要求分析VLSE介导的抗体逃避的IGM需求。拟议的工作具有创新性，因为它涉及对储层小鼠的重新感染，并对B. burgdorferi产生积极的体液反应，以解决VLSE启动保护的保护问题，并利用各种VLSE Mutant B. Burgdorferi Clones感染Tick Vector和Host host Reservoir。 这种方法可能会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。