Borrelia gene products critical for natural infection cycle

描述(由申请人提供)：为了确定莱姆病预防的新治疗靶点，我们建议分析在扁虱中高度诱导的伯氏疏螺旋体基因产物的作用。伯氏杆菌在自然界中通过涉及小型啮齿动物和硬蜱的复杂的地方性循环而繁衍生息。未成熟的扁虱从受感染的宿主那里获得病原体，通过途径维持伯氏杆菌，并在随后的血餐中将其传播给NAOVE宿主。我们假设，螺旋体基因是优先诱导的特定阶段的微生物生命周期在硬蜱对维持病原体在自然界中是重要的。由于许多由壁虱诱导的螺旋体蛋白也可能暴露在病原体表面，因此伯氏杆菌的传播应该受到针对它们的特异性抗体的影响。我们将使用伯氏杆菌模型基因bb0323、bb0246、bba62和bba52来开发这一范例，其中许多基因定位于螺旋体表面，并在特定时间和特定组织中上调。首先，我们将探索基因的定向突变对螺旋体生命周期的影响，以确定特定伯氏杆菌基因产物的相对重要性，并为后续的抗体阻断研究确定潜在的靶点。然后，我们将专注于重要的螺旋体基因，并评估针对选定的伯氏杆菌基因产物的抗体是否中断了微生物的生命周期，并导致宿主免疫保护。我们还将评估扁虱诱导的螺旋体蛋白的功能，重点是病原体与病媒之间的相互作用。这些信息将有助于澄清一种持续存在于各种宿主和媒介组织中的细菌的适应策略，并可能为制定扰乱螺旋体生命周期的预防措施提供新的目标。与公共卫生相关：7.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，在自然界中通过复杂的壁虱-啮齿动物感染循环得以维持。我们建议表征伯氏杆菌基因产物的功能作用，这些基因产物优先在硬蜱中诱导，并对病原体的持久性和传播至关重要。这些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.