Microbial Determinants of Clinical Heterogeneity in Lyme Disease

莱姆病是一种新兴的公共挑战，由于其发病率不断增加，地理范围不断扩大， 以及可能涉及皮肤、神经系统、心脏和关节的异质性临床表现。的 该疾病由疏螺旋体属的螺旋体（以前称为伯氏疏螺旋体 广义组），一个包含20多个物种的多样化组，其中四个通常影响人类。 临床疾病根据感染的种类而不同，但介导的特定微生物因素 这些影响是未知的。为了识别这些基因，候选人和共同导师已经开始进行 疏螺旋体属的基因组关联研究从病人身上。这些初步研究显示， 许多有希望的候选基因座与莱姆病的不同临床表现相关。 该提案是一个职业发展奖，提供了一个独立的途径，包括一个 24-一个月的辅导阶段，然后是24个月的独立阶段。在目标1中，候选人将进行 使用短和长读段序列的混合组装进行全基因组测序， 数百种疏螺旋体属的组装体。从病人的基因组，并执行进化和人口 基因分析，以确定可能影响临床表现的变异。在目标2中，候选人将 进行莱姆病螺旋体的遗传关联研究，以确定相关的微生物脂蛋白 有明显的临床表现作为本目标的一部分，候选人将开发估算方法， 公开可用的基因组数据，并开发靶向捕获方法， 测序而无需微生物培养。在目标3中，候选人将描述 使用实验室模型确定新鉴定的基因座的优先子集的发病机制。 候选人是一名医生，科学家，现任传染病临床和研究员， 马萨诸塞州总医院（MGH），对蜱传疾病发病机制感兴趣并具有相关背景 和基因组学。拟议的培训和研究计划将在初级导师的指导下进行 博士Pardis Sabeti和二级导师John Leong博士、艾伦斯蒂尔博士和Klemen Strle博士。导师 团队汇集了在微生物基因组学方面具有互补专业知识的领先研究人员（Sabeti博士）， 细菌发病机制（梁博士）和莱姆病的临床研究（Strle博士和Steere博士）。工作 将在MGH，Broad研究所和塔夫茨大学的支持，合作环境中进行 这将促进培训和研究。完成拟议的计划将使候选人能够领导一个 一个独立的，NIH资助的研究项目，进行莱姆的基础，转化和临床研究 疾病和其他蜱传病原体。

Lyme disease is an emerging public challenge due to its increasing incidence, expanding geographic range, and heterogeneous clinical manifestations that may involve the skin, nervous system, heart, and joints. The disease is caused by spirochetes of the genus Borreliella (previously referred to as the Borrelia burgdorferi sensu lato group), a diverse group that contains over 20 species, four of which commonly affect humans. Clinical disease varies on the basis of the infecting species, yet the specific microbial factors that mediate these effects are not known. To identify such genes, the candidate and co-mentors have begun conducting genomic association studies of Borreliella spp. from patients. These preliminary studies have revealed a number of promising candidate loci that are associated with distinct clinical manifestations of Lyme disease. This proposal is a career development award that provides a pathway to independence and includes a 24-month mentored phase followed by a 24-month independent phase. In Aim 1, the candidate will conduct whole genome sequencing using hybrid assembly of short- and long-read sequences to produce finished assemblies for hundreds of Borreliella spp. genomes from patients and perform evolutionary and population genetic analyses to identify variants that may influence clinical manifestations. In Aim 2, the candidate will conduct genetic association studies of Lyme disease spirochetes to identify microbial lipoproteins associated with distinct clinical manifestations. As a part of this Aim, the candidate will develop imputation methods for publicly available genomic data and also develop target capture methods that enable whole-genome sequencing without microbial culture. In Aim 3, the candidate will characterize the mechanisms of pathogenesis of a prioritized subset of the newly-identified loci using laboratory models. The candidate is a physician-scientist and current Clinical and Research Fellow in Infectious Disease at Massachusetts General Hospital (MGH) with an interest and background in tick-borne disease pathogenesis and genomics. The proposed training and research plan will take place under the guidance of primary mentor Dr. Pardis Sabeti and secondary mentors Dr. John Leong, Dr. Allen Steere, and Dr. Klemen Strle. The mentor team brings together leading investigators with complementary expertise in microbial genomics (Dr. Sabeti), bacterial pathogenesis (Dr. Leong), and clinical studies of Lyme disease (Dr. Strle and Dr. Steere). The work will be carried out in a supportive, collaborative environment at MGH, the Broad Institute, and Tufts University that will foster training and research. Completion of the proposed plan will position the candidate to lead an independent, NIH-funded research program that performs basic, translational, and clinical studies of Lyme disease and other tick-borne pathogens.