Impact of Antibiotics and Vaccines on the in vivo Evolution of S. pneumoniae

抗生素和疫苗对肺炎链球菌体内进化的影响

• 批准号: 7895507
• 负责人: Garth D. Ehrlich
• 金额: $ 63.94万
• 依托单位: ALLEGHENY-SINGER RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895507
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adherence; Alleles; Animal Model; Antibiotic Resistance; Antibiotics; Back; Biochemical; Bioinformatics; Biological; Biological Assay; Brain; Candidate Disease Gene; Cell surface; Cessation of life; Child; Chinchilla (genus); Clinical; Conjugate Vaccines; Country; DNA; Data; Day center care; Disease; Disease Outbreaks; Disorder by Site; Distant; Environment; Epidemiologic Studies; Epidemiology; Evolution; Exhibits; Fostering; Frequencies; Genes; Genetic; Genetic Determinism; Genetic Engineering; Genetic Recombination; Genome; Genome Stability; Genomics; Genotype; Geographic Locations; Goals; Grouping; Human; In Vitro; Incidence; Infection; Infectious Agent; Infectious Arthritis; Investigation; Learning; Life; Measures; Meningitis; Microbial Biofilms; Minority; Modeling; Molecular; Mus; Nasopharynx; Nature; Otitis Media; Parents; Pathogenicity; Patients; Pattern; Penicillin Resistance; Penicillins; Phenotype; Pneumonia; Polysaccharides; Population; Prevalence; Production; Research; Research Institute; Research Proposals; SP1 gene; School-Age Population; Sepsis; Series; Serotyping; Site; Source; Sterility; Streptococcus pneumoniae; Structure; Techniques; Testing; Time; Tissues; Trees; Universities; Vaccines; Virulence; Work; abstracting; base; capsule; comparative; comparative genomics; design; disease phenotype; ear infection; fitness; genome sequencing; hospice environment; human disease; in vivo; in vivo Model; insight; intraperitoneal; member; metabolomics; novel; pandemic disease; pathogen; pressure; progenitor; programs; research study; resistant strain; response; success; tissue culture

ABSTRACT Streptococcus pneumoniae has remained one of the major causative agents of potentially life threatening human disease in our era. Nevertheless, introduction of antibiotics (penicillin) and ¿ more recently ¿ the conjugate vaccine provoked major evolutionary changes in the structure of natural populations of this pathogen. The purpose of this research proposal is to combine the power of whole genome sequencing (WGS) and epidemiology to obtain insights into the mechanisms by which antibiotic resistant and non-vaccine type pneumococcal lineages emerged in the in vivo environment. The studies will have three foci of concentration. Project I. Three highly penicillin resistant pneumococcal (PRPn) clones: ST-1, ST-2 and ST-3, each with a unique sequence type (MLST) and capsular type have achieved pandemic spread and appear to remain stable over long times and distant geographic sites of isolation. Such genetic stability in a highly recombinogenic pathogen is unusual and it contrasts with the well documented diversity of penicillin susceptible pneumococci. The purpose of this project is to use whole genome sequencing (WGS) to better document and understand the nature and mechanisms of genetic stability in these three PenR clones. Project II. An outbreak investigation in an AIDS hospice identified members of the PenR clone ST-1 as causative agents of the disease. All but two of the 11 single patient isolates expressed capsular polysaccharide 23F typical of this clone. However, 2 isolates produced capsular type 3 which was associated with a tremendous (106 fold) increase in virulence measured in mouse IP models. The purpose of these studies is to use WGS ¿ in combination with the appropriate in vitro complementation experiments ¿ to identify genetic determinants of virulence produced ¿ in vivo ¿ in such a spontaneous ¿experiment of nature¿. Project III. Pneumococcal strains expressing the non-vaccine type (NVT) capsular polysaccharides, such as 11A, 6A or 19A have been identified as minority components of the nasopharyngeal flora of children attending Day Care Centers ¿ even before the introduction of the conjugate vaccine. WGS will be used to test if the emergence of these strains from minority to majority status in the nasopharynx and from colonizers to disease causing strains ¿ is accompanied by changes in genetic makeup

抽象的 肺炎链球菌仍然是 在我们时代，潜在威胁人类疾病的生命。然而，引入 抗生素（青霉素）和最近的结合疫苗引起了主要的疫苗 该病原体自然种群结构的进化变化。 该研究建议的目的是结合整个基因组测序的力量 （WGS）和流行病学，以了解抗生素的机制 体内出现抗性和非疫苗类型的肺炎球菌谱系 环境。研究将具有三个浓度焦点。 项目I。三个高度青霉素耐药性肺炎球菌（PRPN）克隆：ST-1， ST-2和ST-3，每种都具有独特的序列类型（MLST）和囊类型 达到了大流行的扩散，并且似乎在长期内保持稳定，并且遥远 隔离的地理位置。高度重组病原体中的这种遗传稳定性 是不寻常的，它与易感的青霉素的多样性形成鲜明对比 该项目的目的是将整个基因组测序（WGS）用于 更好地记录并了解这些遗传稳定性的性质和机制 三个佩尔克隆。 项目II。在艾滋病临终关怀中进行的爆发调查确定了 PENR克隆ST-1作为疾病的灾难性药物。除11个单曲中的两个外 患者分离株表达该克隆典型的囊囊多糖23F。但是，2 分离株产生的囊型3与巨大（106倍）有关 在小鼠IP模型中测得的病毒增加。这些研究的目的是 将WGS�与适当的体外完成实验结合使用» 在这种赞助商中鉴定在体内产生的病毒的遗传决定因素 自然实验。 项目三。表达非疫苗类型（NVT）的肺炎球菌菌株 囊囊多糖，例如11a，6a或19a已被确定为少数 参加日托中心的儿童鼻咽菌群的组成部分甚至 在引入结合疫苗之前。 WGS将用于测试是否 这些菌株从少数族裔到多数状态的出现以及来自 殖民菌株引起菌株»是通过基因组成的变化来实现的

项目成果

Species-Level Profiling of Ixodes pacificus Bacterial Microbiomes Reveals High Variability Across Short Spatial Scales at Different Taxonomic Resolutions.

太平洋硬蜱细菌微生物组的物种水平分析揭示了不同分类分辨率下短空间尺度的高度变异性。

• DOI: 10.1089/gtmb.2021.0088
• 发表时间: 2021
• 期刊: Genetic testing and molecular biomarkers
• 影响因子: 1.4
• 作者: Socarras,KaylaM;Earl,JoshuaP;Krol,JaroslawE;Bhat,Archana;Pabilonia,Max;Harrison,MeghanH;Lang,StevenP;Sen,Bhaswati;Ahmed,Azad;Hester,Michael;Mell,JoshuaChang;Vandegrift,Kurt;Ehrlich,GarthD
• 通讯作者: Ehrlich,GarthD

Genetic Stabilization of the Drug-Resistant PMEN1 Pneumococcus Lineage by Its Distinctive DpnIII Restriction-Modification System.

• DOI: 10.1128/mbio.00173-15
• 发表时间: 2015-06-16
• 期刊: mBio
• 影响因子: 6.4
• 作者: Eutsey RA;Powell E;Dordel J;Salter SJ;Clark TA;Korlach J;Ehrlich GD;Hiller NL
• 通讯作者: Hiller NL