Linking within- and between-host dynamics in tracking recent Mycobacterium tuberculosis transmission

项目摘要/总结 玛丽南希Séraphin，博士，是一个研究助理教授在佛罗里达大学（UF），系 医学，以及与UF新兴病原体研究所（UF-EPI）和临床和 翻译科学研究所（UF-CTSI）。Séraphin博士在过去的七年里， 博士后，获得结核病（TB）分子流行病学技能。她有将基因分型和 全基因组序列（WGS）与患者临床数据，以调查结核病疫情。她有九个肺结核 出版物，6作为主要作者。在短期内，这个K01奖将提供培训和专业 基因组学和生物信息学的发展机会。Séraphin博士的长期目标是成为领导者 在传染病分子流行病学方面，重点是结核病。环境：Sérapin博士将执行K01 在多学科指导委员会的指导下进行研究。每个导师都是各自领域的领导者 领域首席导师是Marco Salemi博士，他是系统发育、计算和进化生物学方面的专家， 凯尔罗德博士是结核病遗传学、发病机理和诊断方面的专家。Séraphin博士还将获得 在基因组学和生物信息学方面接受正式培训，并获得研究领导能力和研究技能。 研究：结核分枝杆菌（Mtb）是一种非常成功的病原体，估计有1000万 每年新诊断出结核病的人数。快速诊断、有效治疗和接触者追踪是公开的 降低结核病发病率和死亡率的卫生干预措施。通过WGS对培养物进行常规菌株监测- 确诊的结核病病例有助于迅速发现和控制疫情， 社区.更重要的是，快速检测疫情可确保及时识别最近发生的 受感染的接触者可以从预防中受益。不幸的是，接触者追踪活动目前高度 效率低下，因为结核病规划很难识别和针对20%的结核病病例， 次要情况（即，超级传播者）。如果我们能够利用这些资源， 广泛的Mtb宿主内遗传多样性（WHD），可以用深度WGS进行分析。因此，我们建议 评估结核分枝杆菌深层WGS作为人与人之间传播的更高分辨率标记物的效用， 蔓延具体来说，我们建议首先评估WHD传输的变化（即，瓶颈大小）下 不同的肾上腺素方案（目标1）。WHD测量可能会受到实验室处理的干扰， 标本和单基因组/样品分析。因此，我们将按痰液评估WHD测量偏倚 净化、传代培养和痰液采样（目标2）。最后，我们会进行试验研究，测试 跟踪WHD传播以检测新发Mtb传播和超级传播者（目标3）。拟议 研究和培训活动将成功定位Séraphin博士的第一个R01和一个独立的 作为研究科学家的职业生涯。

PROJECT ABSTRACT/SUMMARY Marie Nancy Séraphin, PhD, is a Research Assistant Professor at the University of Florida (UF), Department of Medicine, and a trainee affiliated with both the UF Emerging Pathogens Institute (UF-EPI) and Clinical and Translational Science Institute (UF-CTSI). Dr. Séraphin has spent the last seven years, including two as a postdoc, acquiring tuberculosis (TB) molecular epidemiology skills. She has experience linking genotyping and whole genome sequence (WGS) with patient clinical data to investigate TB outbreaks. She has nine TB publications, six as the lead author. In the short-term, this K01 award will provide training and professional development opportunities in genomics and bioinformatics. Dr. Séraphin's long-term goal is to become a leader in infectious diseases molecular epidemiology, focusing on TB. Environment: Dr. Séraphin will perform her K01 research with guidance from a multidisciplinary mentoring committee. Each mentor is a leader in their respective field. The lead mentors are Dr. Marco Salemi, an expert in phylogenetic, computational, evolutionary biology, and Dr. Kyle Rohde, an expert in TB genetics, pathogenesis, and diagnostics. Dr. Séraphin will also receive formal training in genomics and bioinformatics and acquire research leadership and grantsmanship skills. Research: Mycobacterium tuberculosis (Mtb) is an incredibly successful pathogen, with an estimated 10 million people newly diagnosed with TB annually. Rapid diagnosis, effective treatment, and contact tracing are public health interventions that decrease TB morbidity and mortality. Routine strain surveillance by WGS of culture- confirmed TB cases facilitates the rapid detection and control of outbreaks to prevent further transmission in communities. More importantly, the rapid detection of outbreaks assures the timely identification of recently infected contacts that can benefit from prophylaxis. Unfortunately, contact tracing activities are currently highly inefficient as TB programs struggle to identify and target efforts towards the 20% of TB cases that generate secondary cases (i.e., super spreaders). This critical public health function could be improved if we capitalize on the extensive Mtb within-host genetic diversity (WHD) that can be profiled with deep WGS. Thus, we propose to assess the utility of Mtb deep WGS as a higher resolution marker of person-to-person transmission and super spreading. Specifically, we propose first assessing variation in WHD transmission (i.e., bottleneck size) under diverse epi scenarios (Aim 1). WHD measurement is likely to be confounded by laboratory processing of specimens and single genome/sample analysis. Thus, we will assess WHD measure bias by sputum decontamination, subculturing, and sputum sampling (Aim 2). Finally, we will test in a pilot study the feasibility of tracking WHD transmission to detect de novo Mtb transmission and superspreaders (Aim 3). The proposed research and the training activities will successfully position Dr. Séraphin for her first R01 and an independent career as a research scientist.