Genetic modulators of serum resistance in Neisseria gonorrhoeae

项目摘要 淋病奈瑟菌感染率的增加和抗生素耐药性的传播迫切需要 对公众健康的威胁。支持逃避宿主免疫反应的基因和途径的知识 为了制定新的监测、预防和治疗策略，需要建立一个新的感染机制。尽管 我们对一些淋球菌基因和等位基因的理解，赋予抵抗血清介导的杀伤， 关于影响血清抗性变化的因素，仍然存在重大的知识差距。我们缺乏 临床分离株耐药途径的系统评价：我们对 血清抵抗力的遗传决定因素这些疾病的患病率和系统发育分布情况如何？ 抗性基因和等位基因？在本提案中，我们通过一项全面战略来解决这些差距， 链接实验和计算鉴定有助于血清抵抗的遗传变异， 定义了它们在> 16，000个临床分离株基因组序列的数据集中的分布。 本项目的总体目标是系统地确定N. 淋病我们将通过三个具体目标来实现这一目标，这些目标建立在已经制定的战略基础上， 在我们定义抗生素耐药性遗传基础的工作中，以及数十年来研究抗生素耐药性机制的工作中， 血清抵抗在目标1中，我们将利用我们收集的数百个N.淋病 以确定血清抗性的表型范围，并确定 使用遗传学、统计学方法和转化的组合来分析血清抗性的贡献者。 我们的初步数据支持这一目标，在120例受试者中进行了全基因组关联研究， 临床分离物鉴定已知和新的候选遗传变异，有助于血清耐药性。在 目的2，我们将来自多个遗传谱系的血清敏感分离株在混合人血清中传代， 确定有助于血清抵抗的因素，并描述基因组背景在形成 抵抗的进化轨迹在目标3中，我们将描述患病率和系统发育分布， 血清抵抗的遗传调节剂的分布-结合文献中的那些与目标中确定的那些 1和2-在一组> 16，000个临床分离株中，我们有基因组序列。 该项目汇集了主要调查人员的互补和非重叠的专门知识， 生物学和遗传学研究。淋病，将血清抗性研究（刘易斯和拉姆博士）与ge- 经济学（格拉德博士）。

PROJECT SUMMARY The increasing rate of infection and spread of antibiotic resistance in Neisseria gonorrhoeae poses an urgent threat to public health. Knowledge of the genes and pathways that support evasion of the host immune response and enable infection is needed to develop new strategies for surveillance, prevention, and treatment. Despite our understanding of some of the gonococcal genes and alleles that confer resistance to serum-mediated killing, significant knowledge gaps remain regarding the factors that influence the variation in serum resistance. We lack a systematic evaluation of the pathways to resistance in clinical isolates: how complete is our understanding of the genetic determinants of serum resistance? What is the prevalence and phylogenetic distribution of these resistance genes and alleles? In this proposal, we address these gaps through a comprehensive strategy that links experimental and computational identification of genetic variants that contribute to serum resistance and defines their distribution in a dataset of >16,000 clinical isolate genome sequences. The overall goal of this project is to systematically define the genetic contributors to serum resistance in N. gonorrhoeae. We will achieve this goal through three specific aims, building on strategies that have been suc- cessful in our work defining the genetic basis of antibiotic resistance and decades studying the mechanisms of serum resistance. In Aim 1, we will leverage our collection of hundreds of clinical isolates of N. gonorrhoeae from across the species phylogeny to define the phenotypic range of serum resistance and determine the genetic contributors to serum resistance using a combination of phylogenetics, statistic methods, and transformation. Our preliminary data supports this aim, with a genome-wide association study using serum resistance in 120 clinical isolates identifying known and novel candidate genetic variants that contribute to serum resistance. In Aim 2, we will passage serum susceptible isolates from multiple genetic lineages in pooled human serum to determine factors that contribute to serum resistance and describe the role of genomic background in shaping the evolutionary trajectories to resistance. In Aim 3, we will characterize the prevalence and phylogenetic distri- bution of genetic modulators of serum resistance—combining those in the literature with those identified in Aims 1 and 2—in a set of >16,000 clinical isolates for which we have genome sequences. This project brings together the complementary and non-overlapping expertise of leading investigators in the biology and genetics of N. gonorrhoeae, linking the study of serum resistance (Drs. Lewis and Ram) with ge- nomics (Dr. Grad).