Evolution and pathogenesis of serotype V group B Streptococcus in humans
人类血清型 B 型链球菌的进化和发病机制
基本信息
- 批准号:10355538
- 负责人:
- 金额:$ 19.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-02-17 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdherenceAdultAgeAntibiotic ProphylaxisAreaArginine deiminaseBacteremiaBloodCenters for Disease Control and Prevention (U.S.)CharacteristicsClinicalCollectionComplexDataDevelopmentDiseaseEpidemiologyEventEvolutionExposure toFoundationsFunctional disorderFutureGene ExpressionGene Expression RegulationGenerationsGenesGenetic RecombinationGenomeGenomicsGoalsHumanImmune responseIn VitroInfantInfectionInvestigationKnowledgeMeasuresMediatingMedicalMembrane ProteinsMeningitisModelingMutationNeonatalPathogenesisPathogenicityPathway interactionsPatientsPhenotypePilumPolysaccharidesPopulationPregnancyPublic HealthRegulationRegulator GenesReportingResearchRoleSepsisSerotypingSerumStreptococcus Group BSurveillance ProgramSystemTestingUnited States National Institutes of HealthVirulenceage groupbacterial genome sequencingcapsulecross reactivitydesigndisorder preventionearly onsetgenetic regulatory proteinimprovedin vivoinnovationinsightintrapartummouse modelmutantpathogenpathogenic bacteriapressurescreeningtranscriptometranscriptome sequencingtranscriptomics
项目摘要
PROJECT SUMMARY
Emergence and evolution of bacterial pathogens in humans is the result of a complex interplay between
bacterial factors and the host immune response. Streptococcus agalactiae (group B Streptococcus, GBS)
emerged in the late 1960s and early 1970s as a frequent cause of sepsis and meningitis in infants <90 days of
age. Twenty years later, GBS was also recognized as a significant cause of disease in adults. Serum cross-
reactivity to the GBS capsular polysaccharide (CPS) led to the recognition of 10 CPS types (Ia/Ib, II-IX). The
epidemiology of infant disease is defined by GBS strains of CPS Ia and III and much research has been
devoted GBS pathogenesis and disease prevention in this age group. In contrast, adult disease is dominated
by strains of CPS type IV and V of which we understand little of the bacterial mechanisms contributing to
disease. Combined with the fact that of the ~30,000 cases of invasive GBS disease that occur annually in the
US two-thirds occur in adults, a major knowledge gap exists in our understanding of adult GBS disease
mechanisms. We previously performed one of the only studies to examine CPS V GBS and discovered that
the majority (>85%) are of a single sequence type (ST), ST1, and evolve by small genetic changes
(mutations). Here, we extend our previous analysis to include CPS V GBS strains isolated at the beginning of
the rise in adult GBS disease. Combined with our previous analysis, our data indicate that “early” (pre-1992)
CPS V GBS disease strains were more likely to be ST2 compared to contemporary CPS V GBS among which
ST1 predominates. In addition, we have identified genes encoding an unstudied two-component gene
regulatory system (TCS) as highly polymorphic within the ST1 population consistent with a critical role in CPS
V GBS pathogenesis. These data form the basis of this proposal which seeks to test the hypothesis that ST1
GBS have altered host-pathogen interaction compared to non-ST1 strains owing to differences in gene content
and global gene regulation. Using RNA-sequencing following exposure to human blood ex vivo and models of
GBS colonization and disease, Specific Aim 1 will determine the contribution of gene regulatory differences
between ST1 and non-ST1 GBS that contribute to differences in host-pathogen interaction and dominance of
ST1 among contemporary CPS V GBS. In Specific Aim 2, we test the hypothesis that the identified TCS
contributes to ST1 phenotypic characteristics and predominance among CPS V GBS. We will generate
isogenic deletion mutants and compare transcriptomes to the parental strains using RNA-sequencing to define
the key regulatory targets of the TCS. Subsequently, we will correlate differences in gene regulation to
differences in host-pathogen interaction using models of GBS colonization and disease. Completion of these
studies will provide critical new information regarding CPS V GBS disease in adults and serve as a model for
investigation of other CPS types. Moreover, the proposed studies are designed to generate key preliminary
data needed for deeper investigations into GBS emergence and pathogenesis in humans.
项目摘要
人类细菌病原体的出现和进化是以下因素之间复杂相互作用的结果:
细菌因素和宿主免疫反应。无乳链球菌(B组链球菌,GBS)
在20世纪60年代末和70年代初出现,作为<90天婴儿败血症和脑膜炎的常见原因,
年龄20年后,GBS也被认为是成人疾病的重要原因。血清交叉-
对GBS荚膜多糖(CPS)的反应性导致识别10种CPS类型(Ia/Ib,II-IX)。的
婴儿疾病的流行病学是由CPS Ia和III的GBS菌株定义的,
致力于该年龄组GBS的发病机制和疾病预防。相比之下,成人疾病占主导地位
我们对CPS IV型和V型菌株的细菌机制知之甚少,
疾病结合以下事实,即在美国每年发生的约30,000例侵袭性GBS疾病中,
美国三分之二发生在成年人中,我们对成人GBS疾病的理解存在重大知识差距
机制等我们以前进行了一项研究,以检查CPS V GBS,并发现,
大多数(>85%)是单一序列类型(ST),即ST 1,并通过小的遗传变化进化
(突变)。在这里,我们扩展了我们以前的分析,包括CPS V GBS菌株分离的开始,
成人GBS疾病的增加。结合我们之前的分析,我们的数据表明,“早期”(1992年以前)
与当代CPS V GBS相比,CPS V GBS疾病菌株更可能是ST 2,其中
ST 1占主导地位。此外,我们还鉴定了编码一个未研究的双组分基因的基因
调节系统(TCS)在ST 1人群中具有高度多态性,与CPS中的关键作用一致
VGBS发病机制。这些数据构成了本提案的基础,该提案旨在检验ST 1
由于基因含量的差异,GBS与非ST 1菌株相比改变了宿主-病原体相互作用
和全球基因调控。在离体暴露于人血液和模型后使用RNA测序,
GBS定植和疾病,特异性目的1将决定基因调控差异的贡献
ST 1和非ST 1 GBS之间的差异,导致宿主-病原体相互作用和优势的差异,
ST 1在当代CPS V GBS中。在具体目标2中,我们检验了以下假设:
有助于ST 1表型特征和CPS V GBS中的优势。我们将产生
等基因缺失突变体,并使用RNA测序将转录组与亲本菌株进行比较,以确定
TCS的主要监管目标。随后,我们将把基因调控的差异与
宿主-病原体相互作用的差异使用GBS定殖和疾病的模型。完成这些
研究将提供有关成人CPS V GBS疾病的重要新信息,并作为
其他CPS类型的调查。此外,拟议的研究旨在产生关键的初步
需要更深入地研究GBS在人类中的出现和发病机制的数据。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Evolving antibiotic resistance in Group B Streptococci causing invasive infant disease: 1970-2021.
- DOI:10.1038/s41390-022-02375-3
- 发表时间:2023-06
- 期刊:
- 影响因子:3.6
- 作者:Sabroske, Elizabeth Marie;Iglesias, Misu Ailin Sanson;Rench, Marcia;Moore, Trevor;Harvey, Hanna;Edwards, Morven;Baker, Carol J.;Flores, Anthony R.
- 通讯作者:Flores, Anthony R.
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Anthony Richard Flores其他文献
Anthony Richard Flores的其他文献
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{{ truncateString('Anthony Richard Flores', 18)}}的其他基金
Defining novel mechanisms of clonal emergence in Group A Streptococcus
定义 A 组链球菌克隆出现的新机制
- 批准号:
10189994 - 财政年份:2021
- 资助金额:
$ 19.5万 - 项目类别:
Evolution and pathogenesis of serotype V group B Streptococcus in humans
人类血清型 B 型链球菌的进化和发病机制
- 批准号:
10217675 - 财政年份:2021
- 资助金额:
$ 19.5万 - 项目类别:
Defining novel mechanisms of clonal emergence in Group A Streptococcus
定义 A 组链球菌克隆出现的新机制
- 批准号:
10368151 - 财政年份:2021
- 资助金额:
$ 19.5万 - 项目类别:
Texas Medical Center Training Program in Antimicrobial Resistance
德克萨斯医学中心抗菌素耐药性培训计划
- 批准号:
10401444 - 财政年份:2019
- 资助金额:
$ 19.5万 - 项目类别:
Texas Medical Center Training Program in Antimicrobial Resistance
德克萨斯医学中心抗菌素耐药性培训计划
- 批准号:
10621908 - 财政年份:2019
- 资助金额:
$ 19.5万 - 项目类别:
Texas Medical Center Training Program in Antimicrobial Resistance
德克萨斯医学中心抗菌素耐药性培训计划
- 批准号:
10160768 - 财政年份:2019
- 资助金额:
$ 19.5万 - 项目类别:
Contribution of LiaFSR to pathogenesis and carriage of group A Streptococcus
LiaFSR 对 A 族链球菌发病机制和携带的贡献
- 批准号:
9605689 - 财政年份:2017
- 资助金额:
$ 19.5万 - 项目类别:
Contribution of LiaFSR to pathogenesis and carriage of group A Streptococcus
LiaFSR 对 A 族链球菌发病机制和携带的贡献
- 批准号:
10082424 - 财政年份:2017
- 资助金额:
$ 19.5万 - 项目类别:
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