The role of tick gut microbiota in Borrelia burgdorferi transmission to mice

摘要 该提案将描述蜱肠道微生物群对疏螺旋体能力的影响 伯氏疏螺旋体，莱姆病病原体，从蜱传播到脊椎动物宿主。我们的 最近的工作（Narasimhan 等人，Cell Host Microbe 15:58-71, 2014）证明蜱肠道微生物群 调节肩胛硬蜱的伯氏疏螺旋体定植。我们的初步数据表明正常 肠道微生物群促进伯氏疏螺旋体有效传播至哺乳动物宿主。这是一个 人类莱姆病背景下的关键事件以及了解蜱肠道微生物群如何影响 疏螺旋体向哺乳动物宿主的传播将揭示预防莱姆病传播的新方法。 在目标 1 中，我们将表征并确定与以下相关的蜱肠道细菌特征： 减少伯氏疏螺旋体向脊椎动物宿主的传播。此外，我们还将开始评估 从康涅狄格州流行地区获得的若虫蜱的微生物组成与我们的研究相关 对实验室饲养的蜱虫的观察。将这些知识应用到未来的实地研究中可能会 提供特定地理区域传播风险的新预测因子/生物标记。 在目标 2 中，我们将对蜱肠道进行转录组分析，以描述分子 伯氏疏螺旋体传播过程中受肠道微生物群影响的蜱传播途径。与一个 关注多达 10 个受肠道微生物群显着改变的基因，我们将确定它们的功能 对伯氏疏螺旋体传播的影响。削弱伯氏疏螺旋体传播的潜在疫苗目标 可以从该功能分析中识别出来。 最后，我们将确定生态失调是否可能调节疏螺旋体毒力的表达谱 基因，还影响螺旋体向宿主的传播。我们将重点关注脂蛋白 编码伯氏疏螺旋体的毒力基因并阐明伯氏疏螺旋体如何产生新的认识 感知蜱肠道环境来调节毒力基因的表达。 这项研究工作将使该领域超越对蜱肠道微生物群的描述性理解， 并揭示蜱肠道细菌对蜱病原体相互作用影响的机制理解 特别是，以及一般的载体-病原体相互作用。蜱肠道微生物群提供了新的 了解伯氏疏螺旋体向小鼠传播的生物学并开发 探索导致莱姆病传播的因素的新范例。

ABSTRACT This proposal will characterize the influence of tick gut microbiota on the ability of Borrelia burgdorferi, the Lyme disease agent, to be transmitted from ticks to the vertebrate host. Our recent work (Narasimhan et al, Cell Host Microbe 15:58-71, 2014) demonstrated that tick gut microbiota modulate B. burgdorferi colonization of Ixodes scapularis. Our preliminary data suggest that normal gut microbiota facilitate efficient B. burgdorferi transmission to the mammalian host. This is a critical event in the context of human Lyme disease and understanding how tick gut microbiota influence Borrelia transmission to the mammalian host will reveal new ways to prevent Lyme disease transmission. In Aim 1 we will characterize and determine tick gut bacterial profiles that are associated with decreased B. burgdorferi transmission to the vertebrate host. Further, we will also begin to assess the microbial compositions of nymphal ticks obtained from endemic regions in Connecticut to co-relate our observations on lab-reared ticks. Application of this knowledge to field studies in future efforts might provide new predictors/biomarkers of transmission risk in specific geographic areas. In Aim 2 we will perform a transcriptome analysis of the tick gut to describe the molecular pathways of the tick that are influenced by gut microbiota during B. burgdorferi transmission. With a focus on up to 10 genes that are significantly altered by gut microbiota we will determine their functional consequence on B. burgdorferi transmission. Potential vaccine targets to impair Borrelia transmission may be identified from this functional analysis. Finally, we will determine if dysbiosis might modulate the expression profiles of Borrelial virulence genes, and additionally influence spirochete transmission to the host. We will focus on the lipoprotein encoding virulence genes of B. burgdorferi and unravel a new understanding of how B. burgdorferi senses the tick gut environment to regulate the expression of virulence genes. This research effort will move the field beyond a descriptive understanding of tick gut microbiota, and unfold a mechanistic understanding of the influence of tick gut bacteria on tick-pathogen interactions in particular, and on vector-pathogen interactions in general. Tick gut microbiota provides a new vantage point to understand the biology of B. burgdorferi transmission to mice and to develop new paradigms to explore the factors that contribute to the spread of Lyme disease.