Genetic modulators of serum resistance in Neisseria gonorrhoeae

淋病奈瑟菌血清抗性的遗传调节剂

• 批准号: 10608700
• 负责人: Yonatan H Grad
• 金额: $ 20.91万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-10 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608700
• 关键词: Address; Alleles; Anabolism; Antibiotic Resistance; Bacterial Antibiotic Resistance; Biological Assay; Biology; Clinical; Collection; Complement; Computing Methodologies; Data; Data Set; Development; Diagnosis; Diagnostic; Disease; Epidemiology; Evaluation; Evolution; Face; Genes; Genetic; Genetic Determinism; Genetic Variation; Genome; Genomics; Goals; Gonorrhea; Human; Immune; Immune response; Immune system; Immunotherapeutic agent; In Vitro; Infection; Invaded; Knowledge; Link; Literature; Mediating; Mutation; Neisseria gonorrhoeae; Organism; Pathogenesis; Pathway interactions; Phenotype; Phylogenetic Analysis; Phylogeny; Physiology; Population; Predisposition; Prevalence; Prevention; Prevention strategy; Public Health; Reporting; Research Personnel; Resistance; Role; Scientist; Serum; Sexually Transmitted Diseases; Shapes; Statistical Methods; Study of serum; Testing; Therapeutic; United States; Variant; Work; bactericide; design; direct application; genetic variant; genome wide association study; genomic locus; genomic tools; high risk; improved; infection rate; lipooligosaccharide; novel; pathogenic bacteria; pressure; prevent; resistance allele; resistance gene; resistance mutation; surveillance strategy; vaccine evaluation

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).

项目总结 淋球菌不断增加的感染率和耐药性的传播构成了一个紧迫的问题 对公众健康的威胁。关于支持逃避宿主免疫反应的基因和途径的知识 制定新的监测、预防和治疗战略需要使感染成为可能。尽管 我们对一些淋球菌基因和等位基因的理解，这些基因和等位基因赋予我们对血清介导的杀戮的抵抗力， 关于影响血清抵抗力变化的因素，仍然存在显著的知识差距。我们缺少 临床分离株耐药途径的系统评估：我们对 血清抵抗力的遗传决定因素？这些细菌的流行率和系统发育分布是什么？ 抗性基因和等位基因？在这项提案中，我们通过一项全面的战略来解决这些差距 联系实验和计算鉴定导致血清抵抗力和 定义了它们在16,000个临床分离基因组序列的数据集中的分布。 该项目的总体目标是系统地确定引起新城疫血清耐药性的遗传因素。 淋病。我们将在已通过的战略的基础上，通过三个具体目标实现这一目标- 我们成功地确定了抗生素耐药性的遗传基础，并对其机制进行了数十年的研究 血清抵抗。在目标1中，我们将利用我们收集的数百株淋病奈瑟菌临床分离株 从物种系统发育来定义血清耐药性的表型范围并确定遗传 使用系统发育、统计学方法和转化相结合的方法对血清耐药性的贡献者。 我们的初步数据支持这一目标，在120人中进行了一项使用血清耐药性的全基因组关联研究 确定导致血清耐药性的已知和新的候选基因变异的临床分离株。在……里面 目的2，我们将从混合人血清中传代来自多个遗传谱系的血清敏感株 确定导致血清抵抗力的因素，并描述基因组背景在形成中的作用 抵抗的进化轨迹。在目标3中，我们将描述该病毒的流行率和系统发育分布。 血清抵抗力的遗传调节因子的发现--将文献中的结果与AIMS中确定的结果相结合 1和2-在一组16,000个临床分离株中，我们有其基因组序列。 该项目汇集了世界上主要研究人员的互补和互不重叠的专业知识。 淋球菌的生物学和遗传学，将血清耐药性的研究(刘易斯博士和拉姆博士)与GE-G-G相联系。 经济学(Grad博士)。