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

蜱肠道微生物群在伯氏疏螺旋体向小鼠传播中的作用

基本信息

批准号：
9977908
负责人：
Erol Fikrig
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-10 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977908
关键词：
Address Antibiotic Resistance Antibiotic Therapy Area Biology Black-legged Tick Borrelia Borrelia burgdorferi Cells Connecticut Data Data Analyses Environment Event Expression Profiling Future Gene Expression Profiling Genes Genome Geographic Locations Glycoproteins Goals Growth Human Impairment Individual Interruption Knowledge Length Life Cycle Stages Lipoproteins Lyme Disease Microbe Molecular Mus Nymph Order Spirochaetales Pathway interactions Physiology Play Population Process Proteins RNA Recombinant DNA Research Reverse Transcriptase Polymerase Chain Reaction Risk Role Sequence Analysis Structure Ticks Vaccines Virulence Work digital disease transmission dysbiosis experimental study field study gastrointestinal epithelium germ free isolator gut bacteria gut colonization gut microbiota immunoregulation in silico insight microbial microbiota migration nano-string pathogen predictive marker prevent transcriptome transmission process vector vector-borne pathogen

项目摘要

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.

摘要这项建议将表征扁虱肠道微生物区系对疏螺旋体能力的影响伯氏杆菌，莱姆病病原体，将从扁虱传播到脊椎动物宿主。我们的最近的研究(Narasimhan等人，细胞宿主微生物15：58-71,2014)证明了壁虱肠道微生物区系调节伯氏巴氏杆菌在肩部硬蜱的定植。我们的初步数据显示正常肠道微生物区系有助于伯氏杆菌向哺乳动物宿主的有效传播。这是一个人类莱姆病背景下的关键事件和了解扁虱肠道微生物区系如何影响疏螺旋体向哺乳动物宿主的传播将揭示防止莱姆病传播的新方法。在目标1中，我们将描述和确定与以下相关的扁虱肠道细菌图谱减少伯氏杆菌对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区获得的若虫的微生物组成与我们的对实验室饲养的扁虱的观察。在今后的工作中将这一知识应用于实地研究可能会提供特定地理区域传播风险的新预测指标/生物标记物。在目标2中，我们将对扁虱肠道进行转录组分析，以描述分子在伯氏杆菌传播过程中受肠道微生物区系影响的壁虱路径。使用一个聚焦于肠道微生物区系显著改变的多达10个基因，我们将确定它们的功能对伯氏杆菌传播的影响。潜在疫苗靶点削弱疏螺旋体传播可以从这一功能分析中确定。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，此外还影响螺旋体向宿主的传播。我们将重点介绍脂蛋白。伯氏杆菌毒力基因的编码及对伯氏杆菌致病机制的新认识感知扁虱肠道环境以调节毒力基因的表达。这项研究工作将使该领域超越对扁虱肠道微生物区系的描述性理解，并从机理上理解了壁虱肠道细菌对壁虱-病原体相互作用的影响尤其是关于病媒-病原体之间的相互作用。扁虱肠道微生物区系提供了一种新的了解伯氏杆菌向小鼠传播的生物学和发展探索导致莱姆病传播的因素的新范式。