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 肺炎链球菌仍然是肺炎的主要病原体之一 然而，在我们这个时代，可能会危及生命的人类疾病。 抗生素（青霉素）和 ¿最近 ¿结合疫苗引发了重大 该病原体自然种群结构的进化变化。 该研究计划的目的是将全基因组测序的力量结合起来 （全基因组测序）和流行病学，以深入了解抗生素的作用机制 体内出现耐药性和非疫苗型肺炎球菌谱系 研究将集中三个重点。 项目 I. 三个高度耐青霉素肺炎球菌 (PRPn) 克隆：ST-1、 ST-2 和 ST-3 各自具有唯一的序列类型 (MLST) 和胶囊类型 实现了大流行的传播，并且似乎在很长一段时间内和遥远的距离内保持稳定 高度重组病原体的遗传稳定性。 这是不寻常的，它与有据可查的青霉素敏感性多样性形成鲜明对比 该项目的目的是利用全基因组测序（WGS）来检测肺炎球菌。 更好地记录和理解这些基因稳定性的本质和机制 三个 PenR 克隆。 项目 II. 艾滋病临终关怀中心的疫情调查确定了 PenR 克隆 ST-1 是该疾病的病原体，11 个单克隆中除两个外均是该疾病的病原体。 然而，患者分离株表达了该克隆的典型荚膜多糖 23F。 分离株产生 3 型荚膜，与巨大的（106 倍）相关 在小鼠 IP 模型中测量到的毒力增加。 使用 WGS ¿结合适当的体外互补实验 ¿ 确定产生毒力的遗传决定因素 ¿体内 ¿以如此自发的方式 ¿自然实验¿ 。 项目 III. 表达非疫苗型（NVT）的肺炎球菌菌株 荚膜多糖，如 11A、6A 或 19A 已被确定为少数 日托中心儿童鼻咽菌群的组成 ¿甚至 在引入结合疫苗之前，将使用全基因组测序（WGS）来测试是否有效。 这些菌株在鼻咽中从少数到多数的出现 致病菌株的定殖者 ¿伴随着基因组成的变化

项目成果

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

通过其独特的 DpnIII 限制性修饰系统对耐药 PMEN1 肺炎球菌谱系进行遗传稳定。

• 发表时间: 2015-06-16
• 影响因子: 6.4
• 作者: Eutsey, Rory A;Powell, Evan;Dordel, Janina;Salter, Susannah J;Clark, Tyson A;Korlach, Jonas;Ehrlich, Garth D;Hiller, N Luisa
• 通讯作者: Hiller, N Luisa

Inhibitors of bacterial tubulin target bacterial membranes in vivo.

细菌微管蛋白抑制剂以体内细菌膜为目标。

• 发表时间: 2013-01-01
• 作者: Foss, Marie H;Eun, Ye;Grove, Charles I;Pauw, Daniel A;Sorto, Nohemy A;Rensvold, Jarred W;Pagliarini, David J;Shaw, Jared T;Weibel, Douglas B
• 通讯作者: Weibel, Douglas B

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。

• 发表时间: 2021-08
• 作者: Socarras, Kayla M;Earl, Joshua P;Krol, Jaroslaw E;Bhat, Archana;Pabilonia, Ma;Harrison, Meghan H;Lang, Steven P;Sen, Bhaswati;Ahmed, Azad;Hester, Michael;Mell, Joshua Chang;Vandegrift, Kurt;Ehrlich, Garth D
• 通讯作者: Ehrlich, Garth D