Borrelia gene products critical for natural infection cycle

描述（由申请人提供）：为了寻找预防莱姆病的新治疗靶点，我们建议分析在蜱中高度诱导的伯氏疏螺旋体基因产物的作用。伯氏疏螺旋体在自然界中通过复杂的地方性动物循环繁殖，其中包括小型啮齿动物和蜱虫。未成熟的蜱虫从被感染的宿主处获得病原体，经尿道维持伯氏疏螺旋体，并在随后的吸血过程中将其传播给未成熟的宿主。我们假设，在蜱虫微生物生命周期的特定阶段优先诱导的螺旋体基因对于维持自然界中的病原体是重要的。由于许多蜱虫诱导的螺旋体蛋白也可能暴露在病原体表面，因此伯氏疏螺旋体的传播应该受到针对它们的特异性抗体的影响。我们将利用模型伯氏螺旋体基因bb0323、bb0246、bba62和bba52来开发这一模式，其中许多基因定位于螺旋体表面，并在特定时间和蜱虫的特定组织中上调。首先，我们将探索基因靶向诱变对螺旋体生命周期的影响，以确定特定伯氏疏螺旋体基因产物的相对重要性，并为后续抗体阻断研究确定潜在靶点。然后，我们将重点关注重要的螺旋体基因，并评估针对选定的伯氏疏螺旋体基因产物的抗体是否会中断微生物生命周期并导致宿主免疫保护。我们还将评估蜱诱导的螺旋体蛋白的功能，重点是媒介-病原体相互作用。这些信息将有助于阐明在多种宿主和载体组织中持续存在的细菌的适应策略，并可能为开发防止螺旋体生命周期中断的预防措施提供新的目标。与公共卫生有关：莱姆病是美国最流行的媒介传播疾病，由伯氏疏螺旋体引起，通过复杂的蜱-啮齿动物感染循环在自然界中维持。我们提出表征伯氏疏螺旋体基因产物的功能作用，这些基因产物在蜱中优先诱导，对病原体的持续存在和传播至关重要。这一信息将有助于开发莱姆病疫苗的新治疗靶点。

DESCRIPTION (provided by applicant): To identify new therapeutic targets for Lyme disease prevention, we propose to analyze the roles of Borrelia burgdorferi gene products that are highly induced in ticks. B. burgdorferi thrives in nature through an intricate enzootic cycle involving small rodents and Ixodes ticks. Immature ticks acquire the pathogen from an infected host, transstadially maintain B. burgdorferi, and transmit it to naove hosts during a subsequent blood meal. We hypothesize that spirochete genes that are preferentially induced at specific stages of the microbial life cycle in ticks are important for sustaining the pathogen in nature. As many of these tick-induced spirochete proteins may also be exposed on the pathogen surface, B. burgdorferi transmission should be influenced by specific antibodies against them. We will develop this paradigm using the model B. burgdorferi genes bb0323, bb0246, bba62 and bba52, many of which are localized on the spirochete surface and are upregulated at specific times and in specific tissues in ticks. First, we will explore the effect of targeted mutagenesis of the genes on the spirochete life cycle to establish the relative importance of specific B. burgdorferi gene products and to identify potential targets for subsequent antibody-blocking studies. We will then focus on important spirochete genes and assess if antibodies directed against selected B. burgdorferi gene products interrupt the microbial life cycle and result in host immunoprotection. We will also assess functions of tick-induced spirochete proteins focusing on vector-pathogen interaction. The information will help clarify the adaptive strategies of a bacterium that persists in a diverse array of host and vector tissues, and may contribute new targets for the development of preventive measures for disruption of the spirochete life cycle. PUBLIC HEALTH RELEVANCE: 7. Lyme disease, the most prevalent vector-borne disease in the United States, is caused by Borrelia burgdorferi, which is maintained in nature through an intricate tick-rodent infection cycle. We propose to characterize the functional roles of B. burgdorferi gene products that are preferentially induced in ticks and are critical for pathogen persistence and transmission. This information will contribute to the development of new therapeutic targets for a Lyme disease vaccine.