Borrelia gene products critical for natural infection cycle

描述（由申请人提供）：为了鉴定用于莱姆病预防的新治疗靶点，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。B。burgdorferi在自然界中通过涉及小型啮齿动物和硬蜱的复杂的地方病循环而茁壮成长。未成熟的蜱从受感染的宿主那里获得病原体，跨时空维持B。burgdorferi，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，优先诱导在特定阶段的微生物的生命周期在蜱是重要的，以维持病原体的性质。由于许多这些蜱诱导的螺旋体蛋白也可能暴露在病原体表面，B。伯氏螺旋体的传播应该受到针对它们的特异性抗体的影响。我们将使用模型B来开发这个范例。Burgdorferi基因BB 0323、BB 0246、BBA 62和BBA 52，其中许多位于螺旋体表面，并在特定时间和蜱的特定组织中上调。首先，我们将探讨基因的定向突变对螺旋体生命周期的影响，以确定特异性B的相对重要性。以确定随后的抗体阻断研究的潜在靶点。然后，我们将集中在重要的螺旋体基因和评估，如果抗体针对选定的B。burgdorferi基因产物中断微生物的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，重点关注媒介与病原体的相互作用。这些信息将有助于澄清细菌的适应性策略，这种细菌存在于各种各样的宿主和载体组织中，并可能为制定预防措施破坏螺旋体生命周期提供新的目标。公共卫生相关性：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，它通过复杂的蜱-啮齿动物感染循环在自然界中维持。我们建议对B的功能角色进行表征。在蜱中优先诱导的并且对于病原体持续存在和传播至关重要的伯氏螺旋体基因产物。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.