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

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(GAS)是引起儿童咽炎最常见的细菌，同时也是引起儿童咽炎和咽炎的主要原因。 化脓性(急性中耳炎、急性鼻窦炎、乳突炎)和非化脓性(后链球菌病 肾小球肾炎和急性风湿热)后遗症。此外，天然气已经成为导致 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。运营商状态 对公众健康具有特别重要的意义，因为携带者是病原体传播到 人口中的其他人。气体运输与咽炎的社区暴发有关， 与携带者密切接触者的医院感染和致命侵袭性疾病。到目前为止，没有 研究已经证明了气体在人体内以载体状态存在时的生理特性。 这项提议的主要目标是确定GAS在转录和基因组上的差异 人类殖民状态：急性感染(患有咽炎的儿童)和携带者状态(无症状 治疗后咽部培养阳性的儿童)。由于在获取纵向样本方面存在挑战 从人类受试者的角度来看，到目前为止还没有这样的分析报告。这些结果不仅将是他们的第一个 但我们预计，这将是对被殖民的人类受试者进行的最直接和最具可比性的分析 GAS在感染和定植的不同阶段。我们假设，当处于载流子状态时，气体 表现出与急性感染状态不同的独特转录图谱。我们希望转录 气体剖面图，以提供有关生物体发生变化的重要信息 在急性感染和携带者之间过渡。此前的研究假设，遗传差异 这两种状态下的生物体之间的差异也可能解释了运输潜力的差异。我们将测试这些 使用纵向人体样本的两个假设。 患有急性气性咽炎的儿童将被招募并纳入这项研究。经过治疗后， 成为气体携带者的儿童将被识别出来。这项提案的具体目标是：1)证明 急性咽炎患者体内GAS的转录谱和基因差异 与从载体中回收的气体进行比较和2)采用体外和组织培养模型进行运输 确定差异表达的基因或基因突变如何影响GAS的定植潜力。总的来说， 这项提议将提供人类宿主中气体载体状态的第一个转录组学数据，并将提供 关于遗传和转录变化的宝贵信息在从 致病到在自然寄主中的唯一定植状态。此外，这些结果还可以推广到其他领域。 将它们与寄主的关系从病原体转变为共生关系的致病细菌物种。

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.