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.

项目摘要/摘要 急性咽炎是儿童和成人寻求急性医疗护理的最常见疾病。 A组链球菌（气）是儿童咽炎最常见的细菌原因，两者都会引起 化脓性（急性中耳炎，急性鼻窦炎，乳突炎）和非支持性（链球菌后 肾小球肾炎和急性风湿热）后遗症。此外，天然气已经成为 严重的侵入性疾病，包括链球菌毒性休克综合征和坏死性筋膜炎。载体状态 气体对公共卫生特别重要，因为运营商是将病原体传播到的储层 人口中的其他人。煤气运输与咽炎的社区暴发有关 与携带者密切接触的个体中的医院感染和致命侵入性疾病。迄今为止，没有 研究证明了气体在人类患者中存在的生理特征。 该提案的主要目的是定义两种气体的转录组和基因组差异 人类定植状态：急性感染（咽炎儿童）和携带者状态（无症状在 治疗后具有阳性咽培养的儿童）。由于获得纵向样品的挑战 从人类受试者那里，迄今为止尚无此类分析的报道。这些结果不仅将是他们的第一个 善良，但我们预计它们将是与人类受试者的最直接和可比的分析 在感染和定殖的不同阶段的气体。我们假设，在载体状态时，气体 表现出与急性感染状态不同的独特转录曲线。我们期望转录 天然气的概况，以提供有关生物发生的变化的重要信息 在急性感染和运输之间过渡。先前的研究提出了遗传差异 在这两种状态下的生物之间，也可能解释了运输电位的差异。我们将测试这些 使用纵向人类样本的两个假设。 急性气咽炎的儿童将被招募并参与研究。治疗后， 将确定成为气体载体的孩子。该提案的具体目标是1）证明 从急性咽炎的个体中回收的气体的转录组谱和遗传差异 与从载体中回收的气体和2）运输的体外和组织培养模型相比 确定差异表达的基因或遗传突变如何影响气体的定殖潜力。全面的， 该提案将提供有关人类宿主中天然气载体状态转录组学的第一个数据，并将提供 从一个遗传和转录变化气体从一个转换时，气体也会发生宝贵的信息 在唯一的天然宿主中的致病状态到定殖状态。此外，这些结果可能会推广到其他 病原细菌物种将其与宿主的关系从病原体转变为共生。