Population Analysis of Pseudomonas aeruginosa Virulence
铜绿假单胞菌毒力群体分析
基本信息
- 批准号:10494190
- 负责人:
- 金额:$ 53.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-12-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AllelesAnimal ModelAreaBacteremiaBacteriaBiological AssayCandidate Disease GeneCell Culture TechniquesCenters for Disease Control and Prevention (U.S.)CharacteristicsClinicalCollectionComplementDiseaseElementsEtiologyFoundationsFutureGenerationsGenesGenomeGenomic approachGenomicsGrowthHumanInfectionIntensive Care UnitsLethal Dose 50LightMediatingModelingMonitorMothsMulti-site clinical studyMusNosocomial InfectionsOutcomePathogenesisPathogenicityPathway interactionsPatientsPerformancePilot ProjectsPlayPopulation AnalysisPrevalencePseudomonas aeruginosaPseudomonas aeruginosa infectionReportingRiskRoleSepsisSeverity of illnessSingle Nucleotide PolymorphismSourceTestingTherapeutic AgentsTherapeutic InterventionVirulenceVirulence FactorsWaxesbasecohortcomparative genomicsgene productgenetic approachhuman old age (65+)insertion/deletion mutationinsightmachine learning modelmachine learning predictionmortalitymouse modelmultidrug-resistant Pseudomonas aeruginosanext generation sequencingnovelnovel therapeuticspathogenic bacteriapredict clinical outcomepredictive modelingprognostic valuepublic health prioritiesresistant strainsequencing platform
项目摘要
Pseudomonas aeruginosa (PA) causes frequent and severe infections in hospitalized patients. In addition,
the prevalence of multidrug-resistant PA is increasing and is now between 15-30% in many areas. Thus, it is
not surprising that the IDSA, WHO, and the CDC have each listed PA as serious public health priority in need
of new therapeutic agents. An age-old question concerning PA is why some strains cause substantially more
aggressive infections than others. The recent application of next generation sequencing platforms to this
problem has begun to provide an explanation by demonstrating that PA genomes differ substantially from
strain to strain. Approximately 10-15% of the genes in a typical PA strain are "accessory," meaning that they
are present in some strains but not others. Likewise, the "core" or conserved genome contains numerous
single nucleotide variants (SNVs) and small insertion-deletions (indels). Although a few of these accessory
genes and core alleles have been characterized and shown to modulate virulence, they represent the "tip of
the iceberg." A systematic examination of strain-to-strain differences in PA is likely to uncover a wealth of novel
virulence-impacting genes and alleles. Identification of these would have several important consequences: (i)
They would dramatically enhance our understanding of PA virulence and the mechanisms by which this
bacterium causes severe disease; and (ii) they would allow one to predict the virulence of PA strains based on
the complement of accessory and core virulence genes/alleles that were present in their genomes.
We hypothesize that application of comparative genomic approaches to large numbers of PA isolates will
identify novel virulence genes/alleles and allow the generation of machine learning models to predict the
virulence of PA isolates based on their genomes. We will perform the following specific aims to test these
hypotheses: (1) Use machine learning models to predict the virulence of PA isolates based upon their
genomic content. (2) Identify accessory genes and core genome SNVs/indels that play a causal role in
virulence. (3) Develop a genome-based model that predicts clinical outcomes in patients with PA
bloodstream infections. The impact of this proposal is twofold. First, it will lay the foundation for future
models that provide valuable prognostic information to clinicians treating PA-infected patients. Second, it will
identify new PA virulence factors that mediate novel pathogenic mechanisms of infection.
铜绿假单胞菌(PA)在住院患者中引起频繁而严重的感染。此外,
耐多药PA的患病率正在上升,目前在许多地区在15-30%之间。因此,它是
毫不奇怪,IDSA、WHO和CDC都将PA列为需要优先考虑的严重公共卫生问题
新的治疗药物。关于PA的一个古老的问题是,为什么一些菌株引起的
比其他人更具侵略性的感染。新一代测序平台在这方面的最新应用
问题已经开始提供一种解释,通过证明PA基因组与
努力工作,努力工作。在一个典型的PA菌株中,大约10%-15%的基因是“附属的”,这意味着他们
在某些菌株中存在,但在其他菌株中不存在。同样,“核心”或保守的基因组包含许多
单核苷酸变异(SNV)和小插入-缺失(INDELs)。尽管这些配件中有一些
基因和核心等位基因已经被表征并被证明可以调节毒力,它们代表了
对PA中品系间差异的系统研究可能会发现大量的小说
影响毒力的基因和等位基因。查明这些因素将产生几个重要后果:(I)
它们将极大地增强我们对PA毒力的理解,以及通过这些机制
细菌会导致严重的疾病;以及(Ii)它们将使人们能够根据以下条件预测PA菌株的毒力
基因组中存在的副毒力和核心毒力基因/等位基因的互补。
我们假设,对大量PA分离株应用比较基因组学方法将
识别新的毒力基因/等位基因,并允许机器学习模型的生成来预测
基于其基因组的PA分离物的毒力。我们将执行以下具体目标来测试这些
假设:(1)使用机器学习模型来预测PA分离株的毒力
基因组内容。(2)确定辅助基因和核心基因组SNV/INDELs在
致命性。(3)开发一种基于基因组的模型来预测PA患者的临床结果
血液感染。这项提议的影响是双重的。首先,它将为未来奠定基础
为临床医生治疗PA感染患者提供有价值的预后信息的模型。其次,它将
确定新的PA毒力因子,以介导新的感染致病机制。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('ALAN R HAUSER', 18)}}的其他基金
Assessing SARS-CoV-2 Variant Evolution in Patients
评估患者中的 SARS-CoV-2 变异进化
- 批准号:
10426993 - 财政年份:2021
- 资助金额:
$ 53.47万 - 项目类别:
Dynamics of Pseudomonas aeruginosa During Bacteremia
菌血症期间铜绿假单胞菌的动态
- 批准号:
10222524 - 财政年份:2020
- 资助金额:
$ 53.47万 - 项目类别:
Dynamics of Pseudomonas aeruginosa During Bacteremia
菌血症期间铜绿假单胞菌的动态
- 批准号:
10042352 - 财政年份:2020
- 资助金额:
$ 53.47万 - 项目类别:
Systems Biology Modeling of Severe Hospital-Acquired Pneumonia
严重医院获得性肺炎的系统生物学模型
- 批准号:
10551467 - 财政年份:2018
- 资助金额:
$ 53.47万 - 项目类别:
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