Genetic modulators of serum resistance in Neisseria gonorrhoeae
淋病奈瑟菌血清抗性的遗传调节剂
基本信息
- 批准号:10608700
- 负责人:
- 金额:$ 20.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAllelesAnabolismAntibiotic ResistanceBacterial Antibiotic ResistanceBiological AssayBiologyClinicalCollectionComplementComputing MethodologiesDataData SetDevelopmentDiagnosisDiagnosticDiseaseEpidemiologyEvaluationEvolutionFaceGenesGeneticGenetic DeterminismGenetic VariationGenomeGenomicsGoalsGonorrheaHumanImmuneImmune responseImmune systemImmunotherapeutic agentIn VitroInfectionInvadedKnowledgeLinkLiteratureMediatingMutationNeisseria gonorrhoeaeOrganismPathogenesisPathway interactionsPhenotypePhylogenetic AnalysisPhylogenyPhysiologyPopulationPredispositionPrevalencePreventionPrevention strategyPublic HealthReportingResearch PersonnelResistanceRoleScientistSerumSexually Transmitted DiseasesShapesStatistical MethodsStudy of serumTestingTherapeuticUnited StatesVariantWorkbactericidedesigndirect applicationgenetic variantgenome wide association studygenomic locusgenomic toolshigh riskimprovedinfection ratelipooligosaccharidenovelpathogenic bacteriapressurepreventresistance alleleresistance generesistance mutationsurveillance strategyvaccine evaluation
项目摘要
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)。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Yonatan H Grad其他文献
emNeisseria gonorrhoeae/em diagnostic escape from a emgyrA/em-based test for ciprofloxacin susceptibility and the effect on zoliflodacin resistance: a bacterial genetics and experimental evolution study
淋病奈瑟菌对基于 gyrA 的环丙沙星敏感性检测的诊断逃逸及对唑立复林耐药性的影响:一项细菌遗传学和实验进化研究
- DOI:
10.1016/s2666-5247(22)00356-1 - 发表时间:
2023-04-01 - 期刊:
- 影响因子:20.400
- 作者:
Daniel HF Rubin;Tatum D Mortimer;Yonatan H Grad - 通讯作者:
Yonatan H Grad
Modelling molecular and culture-based surveillance of tetracycline resistance in emNeisseria gonorrhoeae/em
淋病奈瑟菌四环素耐药性基于分子和培养的监测模型
- DOI:
10.1016/s1473-3099(24)00408-0 - 发表时间:
2024-08-01 - 期刊:
- 影响因子:31.000
- 作者:
Kirstin I Oliveira Roster;Rachel Mittelstaedt;Jordan Reyes;Aishani V Aatresh;Yonatan H Grad - 通讯作者:
Yonatan H Grad
Trends in infection incidence and antimicrobial resistance in the US Veterans Affairs Healthcare System: a nationwide retrospective cohort study (2007–22)
美国退伍军人事务医疗保健系统感染发生率和抗菌药物耐药性趋势:一项全国性回顾性队列研究(2007-22 年)
- DOI:
10.1016/s1473-3099(24)00416-x - 发表时间:
2024-12-01 - 期刊:
- 影响因子:31.000
- 作者:
Thi Mui Pham;Yue Zhang;McKenna Nevers;Haojia Li;Karim Khader;Yonatan H Grad;Marc Lipsitch;Matthew Samore - 通讯作者:
Matthew Samore
Biodiversity and hypervirulence of Listeria monocytogenes
单核细胞增生李斯特菌的生物多样性和超强毒性
- DOI:
10.1038/ng.3515 - 发表时间:
2016-02-24 - 期刊:
- 影响因子:29.000
- 作者:
Yonatan H Grad;Sarah M Fortune - 通讯作者:
Sarah M Fortune
Yonatan H Grad的其他文献
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{{ truncateString('Yonatan H Grad', 18)}}的其他基金
Identification and analysis of compensatory mutations that support the evolution of antibiotic resistance in Neisseria gonorrhoeae
支持淋病奈瑟菌抗生素耐药性进化的补偿突变的鉴定和分析
- 批准号:
10443593 - 财政年份:2020
- 资助金额:
$ 20.91万 - 项目类别:
Identification and analysis of compensatory mutations that support the evolution of antibiotic resistance in Neisseria gonorrhoeae
支持淋病奈瑟菌抗生素耐药性进化的补偿突变的鉴定和分析
- 批准号:
10034093 - 财政年份:2020
- 资助金额:
$ 20.91万 - 项目类别:
Identification and analysis of compensatory mutations that support the evolution of antibiotic resistance in Neisseria gonorrhoeae
支持淋病奈瑟菌抗生素耐药性进化的补偿突变的鉴定和分析
- 批准号:
10219082 - 财政年份:2020
- 资助金额:
$ 20.91万 - 项目类别:
Identification and analysis of compensatory mutations that support the evolution of antibiotic resistance in Neisseria gonorrhoeae
支持淋病奈瑟菌抗生素耐药性进化的补偿突变的鉴定和分析
- 批准号:
10650744 - 财政年份:2020
- 资助金额:
$ 20.91万 - 项目类别:
Genomics approaches to elucidating pathways to antibiotic resistance in Neisseria gonorrhoeae
阐明淋病奈瑟菌抗生素耐药性途径的基因组学方法
- 批准号:
10736734 - 财政年份:2017
- 资助金额:
$ 20.91万 - 项目类别:
Genomics approaches to elucidating pathways to antibiotic resistance in Neisseria gonorrhoeae
阐明淋病奈瑟菌抗生素耐药性途径的基因组学方法
- 批准号:
9367004 - 财政年份:2017
- 资助金额:
$ 20.91万 - 项目类别:
Genomics approaches to elucidating pathways to antibiotic resistance in Neisseria gonorrhoeae
阐明淋病奈瑟菌抗生素耐药性途径的基因组学方法
- 批准号:
10190792 - 财政年份:2017
- 资助金额:
$ 20.91万 - 项目类别:
Genomic epidemiology of Neisseria gonorrhoeae with elevated MICs to cefixime
头孢克肟 MIC 升高的淋病奈瑟菌的基因组流行病学
- 批准号:
8862369 - 财政年份:2013
- 资助金额:
$ 20.91万 - 项目类别:
Genomic epidemiology of Neisseria gonorrhoeae with elevated MICs to cefixime
头孢克肟 MIC 升高的淋病奈瑟菌的基因组流行病学
- 批准号:
9005937 - 财政年份:2013
- 资助金额:
$ 20.91万 - 项目类别:
Genomic epidemiology of Neisseria gonorrhoeae with elevated MICs to cefixime
头孢克肟 MIC 升高的淋病奈瑟菌的基因组流行病学
- 批准号:
8487485 - 财政年份:2013
- 资助金额:
$ 20.91万 - 项目类别:
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