Transcriptomic and Genetic Differences of Group A Streptococcus in Humans: Acute Infection versus Carriage

人类 A 组链球菌的转录组和遗传差异：急性感染与携带

• 批准号: 9975700
• 负责人: Laura Carol Case Cook
• 金额: $ 20.86万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-10 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975700
• 关键词: Acute; Acute Pharyngitis; Adult; Affect; Aftercare; Age; Animal Model; Antibiotics; Antigens; Bacteria; Bacterial Model; Benchmarking; Benign; Caring; Carrier State; Cell Culture Techniques; Characteristics; Child; Clinical; Communities; Conflict (Psychology); DNA Sequence Alteration; Data; Data Set; Development; Disease; Disease Outbreaks; Economic Burden; Enrollment; Event; Exhibits; Future; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genome; Genomics; Goals; Haemophilus influenzae; Human; In Vitro; Individual; Infection; Inflammation; Knowledge; Life Style; Mastoiditis; Medical; Modeling; Molecular; Mucous Membrane; Mutation; Necrotizing fasciitis; Nosocomial Infections; Organism; Otitis Media; Pathogenesis; Pathogenicity; Patients; Persons; Pharyngeal structure; Pharyngitis; Phase; Phenotype; Physiological; Population; Post-Streptococcal Glomerulonephritis; Public Health; Reporting; Rheumatic Fever; Sampling; Serological; Sinusitis; Staphylococcus aureus; Streptococcal Infections; Streptococcus; Streptococcus pneumoniae; Streptococcus pyogenes; Surface; Swab; Symptoms; System; Techniques; Testing; Thinking; Toxic Shock Syndrome; Treatment Failure; Upper respiratory tract; Virulence; Virulent; Work; acute infection; antimicrobial; bacterial genetics; differential expression; extracellular; genome sequencing; human pathogen; human subject; microbiota; microorganism; non-genetic; pathobiont; pathogen; programs; recruit; response; tissue culture; transcriptomics; transmission process; whole genome

PROJECT SUMMARY/ABSTRACT Acute pharyngitis is the most common illness for which children and adults seek acute medical care. Group A streptococcus (GAS) is the most frequent bacterial cause of pharyngitis in children and causes both suppurative (acute otitis media, acute sinusitis, mastoiditis) and non-suppurative (post-streptococcal glomerulonephritis and acute rheumatic fever) sequelae. Furthermore, GAS has emerged as a major cause of severe invasive disease including streptococcal toxic shock syndrome and necrotizing fasciitis. The carrier state of GAS is of particular significance to public health as carriers serve as a reservoir for spread of the pathogen to others in the population. GAS carriage has been associated with community outbreaks of pharyngitis, nosocomial infections and fatal invasive disease in individuals who are close contacts of carriers. To date, no study has demonstrated the physiological characteristics of GAS as it exists in the carrier state in human patients. The main goal of this proposal is to define the transcriptomic and genomic differences of GAS between two states of human colonization: acute infection (in children with pharyngitis) and the carrier state (in asymptomatic children with positive pharyngeal cultures after treatment). Due to the challenge in obtaining longitudinal samples from human subjects, to date there are no reports of such analyses. Not only will these results be the first of their kind, but we anticipate they will be the most direct and comparable analyses from human subjects colonized with GAS during different stages of infection and colonization. We hypothesize that, when in the carrier state, GAS exhibits unique transcriptional profiles that differ from those of the acute infection state. We expect transcriptional profiles of GAS to provide important information regarding the changes the organism undergoes when transitioning between acute infection and carriage. Previous studies have posited that genetic differences between organisms in these two states may also account for differences in carriage potential. We will test these two hypotheses using longitudinal human samples. Children with acute GAS pharyngitis will be recruited and enrolled in the study. Following treatment, children who become GAS carriers will be identified. The specific goals of this proposal are to 1) demonstrate the transcriptomic profiles and genetic differences in GAS recovered from individuals with acute pharyngitis compared to GAS recovered from carriers and 2) employ in vitro and tissue culture models of carriage to determine how differentially expressed genes or genetic mutations affect colonization potential of GAS. Overall, this proposal will offer the first data on the transcriptomics of GAS carrier state in a human host and will provide invaluable information on both the genetic and transcriptional changes GAS undergoes when switching from a pathogenic to colonization state in the only natural host. Furthermore, these results may be generalized to other pathobiont bacterial species that shift their relationship to the host from pathogen to commensal.

项目概要/摘要 急性咽炎是儿童和成人寻求紧急医疗护理的最常见疾病。 A 族链球菌 (GAS) 是儿童咽炎最常见的细菌原因，可引起以下两种情况： 化脓性（急性中耳炎、急性鼻窦炎、乳突炎）和非化脓性（链球菌感染后） 肾小球肾炎和急性风湿热）后遗症。此外，GAS 已成为导致 严重侵袭性疾病，包括链球菌中毒性休克综合征和坏死性筋膜炎。载体状态 GAS 对公共卫生具有特别重要的意义，因为携带者是病原体传播到其他地方的储存库。 人口中的其他人。气体携带与社区咽炎的爆发有关， 与携带者有密切接触的人发生院内感染和致命的侵袭性疾病。迄今为止，没有 研究证明了GAS在人类患者体内以携带状态存在的生理特征。 该提案的主要目标是定义两个基因组之间 GAS 的转录组和基因组差异 人类定植状态：急性感染（患有咽炎的儿童）和携带者状态（无症状 治疗后咽部培养呈阳性的儿童）。由于获取纵向样本的挑战 迄今为止，还没有针对人类受试者进行此类分析的报告。这些结果不仅将是他们的第一个 种类，但我们预计它们将是来自被殖民的人类受试者的最直接和可比较的分析 感染和定植的不同阶段的 GAS。我们假设，当处于载流子状态时，GAS 表现出与急性感染状态不同的独特转录谱。我们期望转录 GAS 的概况，以提供有关有机体在以下情况下发生的变化的重要信息： 急性感染和携带之间的过渡。此前的研究表明，基因差异 这两种状态下的生物体之间也可能导致携带潜力的差异。我们将测试这些 使用纵向人体样本的两个假设。 患有急性 GAS 咽炎的儿童将被招募并参加该研究。治疗后， 成为气体携带者的儿童将被识别。该提案的具体目标是 1) 证明 从急性咽炎个体中恢复的 GAS 转录组图谱和遗传差异 与从载体中回收的 GAS 相比，2) 采用体外和组织培养载体模型来 确定差异表达基因或基因突变如何影响 GAS 的定植潜力。全面的， 该提案将提供有关人类宿主中气体携带状态转录组学的第一个数据，并将提供 关于 GAS 从基因转变时所经历的遗传和转录变化的宝贵信息 在唯一自然宿主中致病至定植状态。此外，这些结果可以推广到其他 将其与宿主的关系从病原体转变为共生的致病细菌物种。