The Role of YebC in persistent infection of the Lyme disease pathogen

YebC 在莱姆病病原体持续感染中的作用

• 批准号: 10622561
• 负责人: X. Frank Yang
• 金额: $ 23.78万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622561
• 关键词: Antibody Therapy; Antigenic Variation; Borrelia; Borrelia burgdorferi; Borrelia burgdorferi Group; Data; Down-Regulation; Gene Expression; Genetic Recombination; Genetic Transcription; Genome; Goals; Humoral Immunities; Immune Evasion; Immune response; Immune signaling; Immunocompetent; In Vitro; Infection; Isopropyl Thiogalactoside; Lipoproteins; Lyme Disease; Mammals; Mediating; Molecular; Mus; Open Reading Frames; OspC protein; Outcome; Pattern; Phase; Process; Public Health; Regulation; Role; SCID Mice; Signal Transduction; Surface; Surface Antigens; Testing; United States; Up-Regulation; Work; chronic infection; differential expression; expectation; improved; mouse model; novel; pathogen; therapeutic target; transcription factor; virtual; virulence gene

PROJECT ABSTRACT Lyme disease has emerged as a major public health threat in the United States. One of the unique features of the Lyme disease pathogen Borrelia (or Borreliella) burgdorferi (B. burgdorferi) infection is its ability to evade immune responses and cause persistent infection in mammalian hosts. Differential expression of surface antigens and VlsE antigen variation are two major strategies evolved by B. burgdorferi to achieve persistence in mammals. During the transition from early to persistent phase of infection when humoral immunity is activated, this spirochetal pathogen downregulates OspC, a major surface antigen that is required for early phase of infection. Concomitantly, B. burgdorferi upregulates VlsE, a surface lipoprotein that undergoes antigen variation in mammalian hosts. How vlsE is differentially regulated and what controls vlsE recombination are not unknown. We recently discovered a hypothetical ORF (BB0025) in the B. burgdorferi genome, encoding a novel regulator YebC that controls vlsE expression. In this application, we will test the hypothesis that YebC orchestrates differential expression of vlsE during the early and persistent phases of infection (Aim 1). We will also examine whether downregulation of ospC requires YebC during mammalian infection. In addition to regulating vlsE expression, we provide preliminary data supporting the hypothesis that YebC is also involved in regulating the process of vlsE recombination. This will be tested in Aim 2. Upon the successful completion of this project, we will have identified a key regulator involving in vlsE regulation and antigen variation. Not only will it fill a major gap in our understanding of how B. burgdorferi upregulates vlsE expression and activate the vlsE recombination in the mammalian host, but also will open up a new avenue for further elucidating how YebC responds to humoral immune response or other host signals to regulates virulence gene expression. Thus, the outcome of this application will significantly advance our understanding immune evasion and persistent infection of B. burgdorferi and other pathogens in general.

项目摘要 莱姆病在美国已成为主要的公共卫生威胁。独特之一 莱姆病病原体的特征（或Borreliella）Burgdorferi（B. burgdorferi）的特征 感染是其逃避免疫反应并引起哺乳动物持续感染的能力 主持人。表面抗原和VLSE抗原变异的差异表达是两个主要的 B. burgdorferi进化的策略以实现哺乳动物的持久性。在过渡期间 当激活体液时，早期到持续感染阶段，这种螺旋体 病原体下调OSPC，这是一种主要的表面抗原，是早期阶段所必需的 感染。同时，B。Burgdorferi上调VLSE，一种经历的表面脂蛋白 哺乳动物宿主的抗原变异。 VLSE如何受到差异调节以及哪些控制VLSE 重组不是未知的。我们最近在B中发现了一个假设的ORF（BB0025）。 Burgdorferi基因组，编码一个控制VLSE表达的新型调节剂YEBC。在这个 应用，我们将测试YEBC策划VLSE差异表达的假设 在感染的早期和持续阶段（目标1）。我们还将检查是否 OSPC的下调需要在哺乳动物感染期间YEBC。除了调节VLSE 表达，我们提供了支持Yebc也参与的假设的初步数据 调节VLSE重组的过程。这将在AIM 2中进行测试。 完成该项目的完成，我们将确定涉及VLSE法规的关键调节器和 抗原变异。我们对B. Burgdorferi的理解不仅填补了一个重大差距 上调VLSE表达并激活哺乳动物宿主中的VLSE重组 将为进一步阐明YEBC如何应对体液免疫的新途径 反应或其他宿主信号调节毒力基因表达。因此，结果的结果 应用将大大提高我们的理解免疫逃避和持续感染 B. burgdorferi和其他病原体的摄入。