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

项目摘要 莱姆病已成为美国主要的公共卫生威胁。其中一个独特的 莱姆病病原伯氏疏螺旋体(或疏螺旋体)的特征 感染是一种逃避免疫反应并导致哺乳动物持续感染的能力 主持人。表面抗原的差异表达和VlsE抗原的变异是两大主要原因 伯氏杆菌为在哺乳动物身上实现持久力而进化出的策略。在从 感染的早期到持续阶段，当体液免疫被激活时，这种螺旋体 病原体下调OspC的表达，OspC是一种主要的表面抗原，在早期阶段是必需的 感染。与此同时，伯氏杆菌上调VlsE，一种经历了 哺乳动物宿主中的抗原变异。VlsE如何进行差异化监管以及由什么控制VlsE 重组并不是未知的。我们最近发现了一个假设的ORF(BB0025)。 Burgdorferi基因组，编码一种新的调节因子YebC，控制VlsE的表达。在这 应用程序中，我们将检验YebC协调VlsE差异表达的假设 在感染的早期和持续阶段(目标1)。我们还将研究是否 在哺乳动物感染期间，SpC的下调需要YebC。除了监管VlsE 表达，我们提供了初步的数据支持的假设，即YebC也参与 调控VlsE重组过程。这将在目标2中进行测试。在成功 这个项目完成后，我们将确定一个参与VlsE监管的关键监管机构，并 抗原变异。它不仅填补了我们对伯氏杆菌如何 上调VlsE在哺乳动物宿主中的表达并激活VlsE重组，但也 将为进一步阐明YebC如何应答体液免疫开辟新的途径 调节毒力基因表达的反应或其他寄主信号。因此，这种情况的结果是 应用将大大提高我们对免疫逃避和持续感染的理解 伯氏杆菌和其他病原体。

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.