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

项目总结/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）是儿童咽炎最常见的细菌原因， 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，天然气已成为一个主要原因， 严重的侵袭性疾病，包括链球菌中毒性休克综合征和坏死性筋膜炎。携带者国家 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的储存库， 人口中的其他人。GAS携带与咽炎的社区爆发有关， 医院感染和致命的侵袭性疾病的个人谁是密切接触的带菌者。至今没有 研究已经证明了GAS在人类患者中以携带者状态存在时的生理特征。 本提案的主要目标是确定两个人之间GAS的转录组学和基因组学差异， 人类定植状态：急性感染（儿童咽炎）和携带状态（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，迄今为止，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，它们将是对人类受试者进行的最直接和最具可比性的分析。 GAS在感染和定殖的不同阶段。我们假设，当处于载流子状态时，GAS 表现出不同于急性感染状态的独特转录谱。我们希望转录 GAS谱提供了关于生物体在以下情况下经历的变化的重要信息： 在急性感染和携带之间过渡先前的研究已经假设基因差异 这两个国家的生物之间的差异也可以解释携带潜力的差异。我们将测试这些 两个假设使用纵向人类样本。 将招募急性GAS咽炎儿童并入组研究。治疗后， 成为GAS携带者的儿童将被识别。本提案的具体目标是：1）证明 急性咽炎患者GAS的转录组学特征和遗传差异 与从载体回收的GAS相比，和2）采用体外和组织培养的携带模型， 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， 该提案将提供关于人类宿主中GAS携带状态的转录组学的第一个数据， 关于GAS在从一个基因组转换到另一个基因组时所经历的遗传和转录变化的宝贵信息。 致病性在唯一的自然宿主中的定殖状态。此外，这些结果可以推广到其他 致病性细菌种类，将它们与宿主的关系从病原体转变为寄生虫。

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.