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.

项目总结

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.