Microbial Determinants of Clinical Heterogeneity in Lyme Disease

莱姆病是一个新兴的公共挑战，因为它的发病率不断上升，地理范围扩大， 临床表现多种多样，可能累及皮肤、神经系统、心脏和关节。这个 该病由伯氏疏螺旋体属(​​)螺旋体(以前称为伯氏疏螺旋体​)引起 Sensu Lato组)，这是一个多样化的组，包含20多种物种，其中4种通常影响人类。 临床疾病根据感染种类的不同而不同，但中介作用的特定微生物因素 这些影响是未知的。为了识别这样的基因，候选人和共同导师已经开始进行 疏螺旋体​​spp.基因组关联性研究从病人那里。这些初步研究揭示了 与莱姆病不同临床表现相关的有希望的候选基因座的数量。 这项提议是一个职业发展奖，提供了一条独立的途径，并包括 24个月的指导阶段，然后是24个月的独立阶段。在目标1中，候选人将进行 利用短读和长读序列的混合组装进行全基因组测序 数以百计的​疏螺旋体​spp.患者的基因组并执行进化和种群 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 具有明显的临床表现。作为这一目标的一部分，候选人将开发用于 公开可用的基因组数据，并开发目标捕获方法，使全基因组 没有微生物培养的测序。在目标3中，候选人将描述 利用实验室模型研究新发现的基因座的优先子集的发病机制。 候选人是一名内科科学家，现任传染病临床和研究员， 马萨诸塞州总医院(MGH)，对壁虱传播疾病的发病机制感兴趣和背景 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 帕迪斯·萨贝蒂博士和二级导师梁约翰博士、艾伦·斯蒂尔博士和克莱门·斯特勒博士。良师益友 团队聚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(萨贝蒂博士) 细菌致病(梁博士)和莱姆病的临床研究(斯特尔博士和斯蒂尔博士)。这项工作 将在麻省理工学院、布罗德研究所和塔夫茨大学的支持性、协作性环境中进行 这将促进培训和研究。完成提议的计划将使候选人能够领导 由美国国立卫生研究院资助的独立研究计划，对莱姆病进行基础、翻译和临床研究 疾病和其他扁虱传播的病原体。

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.