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: 10355538
• 负责人: Anthony Richard Flores
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10355538
• 关键词: Address; Adherence; Adult; Age; Antibiotic Prophylaxis; Area; Arginine deiminase; Bacteremia; Blood; Centers for Disease Control and Prevention (U.S.); Characteristics; Clinical; Collection; Complex; Data; Development; Disease; Epidemiology; Event; Evolution; Exposure to; Foundations; Functional disorder; Future; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic Recombination; Genome; Genomics; Goals; Human; Immune response; In Vitro; Infant; Infection; Investigation; Knowledge; Measures; Mediating; Medical; Membrane Proteins; Meningitis; Modeling; Mutation; Neonatal; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Pilum; Polysaccharides; Population; Pregnancy; Public Health; Regulation; Regulator Genes; Reporting; Research; Role; Sepsis; Serotyping; Serum; Streptococcus Group B; Surveillance Program; System; Testing; United States National Institutes of Health; Virulence; age group; bacterial genome sequencing; capsule; cross reactivity; design; disorder prevention; early onset; genetic regulatory protein; improved; in vivo; innovation; insight; intrapartum; mouse model; mutant; pathogen; pathogenic bacteria; pressure; screening; transcriptome; transcriptome sequencing; transcriptomics

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

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: PEDIATRIC RESEARCH
• 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.