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)。
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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