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).

项目摘要 淋病奈瑟氏菌的感染率增加和抗生素耐药性的扩散是紧急的 对公共卫生的威胁。了解支持宿主免疫反应演化的基因和途径 需要启用感染来制定监视，预防和治疗的新策略。尽管 我们对某些淋球菌基因和等位基因的理解，这些基因会议对血清介导的杀戮的抵抗， 关于影响血清抗性变化的因素，仍然存在很大的知识差距。我们缺乏 对临床分离株中抵抗途径的系统评估：我们对 血清抗性的遗传决定剂？这些的患病率和系统发育分布是什么 抗性基因和等位基因？在此提案中，我们通过一项综合策略来解决这些差距 链接有助于血清耐药性和的遗传变异的实验和计算鉴定 定义它们在> 16,000个临床分离株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定义N. N.的遗传因素。 淋病。我们将通过三个特定目标来实现这一目标，以成功的策略为基础 努力定义抗生素抗性的遗传基础的工作，并研究了数十年 血清抗性。在AIM 1中，我们将利用数百种淋病的临床分离株的收集 从整个物种系统发育中定义血清抗性的表型范围并确定遗传 使用系统发育，统计方法和转化的组合，促进血清耐药性。 我们的初步数据支持了这一目标，通过在120中使用血清抗性的全基因组关联研究 鉴定出有助于血清抗性的已知和新型候选遗传变异的临床分离株。在 AIM 2，我们将从人类血清中的多个遗传谱系中传递血清易感分离株 确定导致血清抗性的因素，并描述基因组背景在塑造中的作用 抗性的进化轨迹。在AIM 3中，我们将表征患病率和系统发育的分散 血清耐药性的遗传调节剂按钮 - 将文献中的遗传调节剂与目标相结合的按钮 1和2-在我们具有基因组序列的一组> 16,000个临床分离株中。 该项目汇集了领先研究人员的完整和不重叠的专业知识 N.淋病的生物学和遗传学，将血清耐药性研究（Lewis和Ram）与GE-联系起来 词汇（Grad博士）。