Factors that influence susceptibility to acute streptococcal pharyngitis

影响急性链球菌性咽炎易感性的因素

• 批准号: 8119697
• 负责人: PATRICIA A RYAN
• 金额: $ 11.29万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-06 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8119697
• 关键词: Acute; Acute Pharyngitis; Address; Adherence; Applications Grants; Bacteria; Bacterial Adhesins; Binding; Cell surface; Cells; Child; Chronic; Complex; Data; Development; Drug Formulations; Environment; Epithelial Cells; Epithelial Receptor Cell; Epitopes; Event; Excision; Exhibits; Gel; Gene Expression; Gene Expression Profile; Genes; Glycoproteins; Human; Individual; Infection; International; Investigation; Longitudinal Studies; Measures; Mediating; Membrane Proteins; Microarray Analysis; Molecular; Monosaccharides; Mucins; Mucous body substance; Oligonucleotide Microarrays; Oral cavity; Organism; Outcome; Pathogenesis; Pattern; Pharyngeal structure; Pharyngitis; Physiological; Play; Positioning Attribute; Predisposition; Preparation; Principal Investigator; Process; Production; Publications; Publishing; Research; Research Project Grants; Respiratory Mucosa; Respiratory System; Respiratory tract structure; Rheumatic Heart Disease; Role; Saliva; Salivary; Sampling; Sialic Acids; Site; Streptococcal Infections; Streptococcus; Streptococcus pyogenes; Surface; Testing; Therapeutic; Tissues; Tonsil; Tonsillar Tissue; Toxin; Transcriptional Regulation; United States National Institutes of Health; Universities; Upper respiratory tract; Virulence; Work; base; design; glycosylation; insight; meetings; pathogen; prevent; public health relevance; receptor; respiratory; saliva mediated; salivary mucins

DESCRIPTION (provided by applicant): Group A streptococci infect through the upper respiratory tract mucosal surface and cause human pharyngitis ("Strep throat"), by first subverting clearance by the respiratory tract mucus and then attaching to the pharyngeal cell. On the molecular level, neither one of these initial events is particularly well understood. Furthermore, very little is known about the factors that influence host susceptibility to such infections. We propose to address this gap by studying one of the earliest interactions between streptococci and humans: the interaction with upper respiratory tract mucus (i.e. saliva). We have previously shown that streptococci specifically bind to the monosaccharide, sialic acid, in commercial available preparations of salivary mucin (the major glycoprotein component of mucus gels), and that the binding to sialic acid is also important in adherence to pharyngeal epithelial cells. Although the upper respiratory tract mucus layer is the site of initial interactions between streptococci and its host, salivary mucus composition has not yet been studied as a factor that influences infection susceptibility. As the first aim of this application, we will determine the concentration of sialic acid in salivary samples from children who exhibit different susceptibilities to streptococcal pharyngitis to determine if a correlation exists between infection rate and salivary composition. We predict that sialic acid concentrations will vary between susceptibility groups, and hypothesize that saliva from individuals who are susceptible to streptococcal carriage or acute infection will contain a higher concentration of sialic acid than non-susceptible individuals. The formulation of this hypothesis is based on previous findings that secretory mucins that coat the upper respiratory mucosa are structurally similar to the surface exposed glycoproteins on underlying tissue. Thus, increased concentrations of sialic acid in salivary mucus will likely reflect an increased number of sialylated receptors on the pharyngeal/tonsillar cells, and this increase in binding epitopes would allow for more efficient colonization of the target tissue. As infection is a dynamic interaction between host and pathogen, it is also important to study how streptococci sense and subsequently react to different host environments. Thus, as a second aim, we propose to examine the transcriptional regulation and gene expression patterns during contact with salivary samples from children with different infection susceptibilities. There are many complex interactions and many potential physiological factors that will play roles in pathogenesis; however little is known about the specific molecular events that occur to streptococci during the interaction with salivary mucus from different children. We predict that the saliva-mediated transcriptome will differ depending on host susceptibility. We hypothesize that genes encoding particular virulence determinants will be upregulated during contact with saliva from infection-susceptible children as compared to saliva from non-carrier individuals. These studies in total may provide initial clues into the reason why certain individuals are more likely than others to develop streptococcal pharyngitis. PUBLIC HEALTH RELEVANCE: One of the long-standing questions regarding streptococcal pharyngitis ("Strep throat") focuses on the reasons why particular children are more susceptible to developing such infections as compared to others. Our study addresses this question from a new perspective and is designed to determine: 1) if increased concentrations of sialic acid in a child's saliva correlates with increased susceptibility to acute pharyngitis or to chronic colonization by streptococci and 2) if contact with saliva from acutely infected children increases streptococcal virulence gene expression. As it estimated that over 600 million cases of pharyngitis occur worldwide annually, and that 3 million children currently suffer from rheumatic heart disease as a result of improper treatment of these infections, identifying factors that increase or decrease a child's susceptibility is an urgent matter and must be addressed if better preventative therapies are to be developed.

描述(申请人提供)：A组链球菌通过上呼吸道粘膜表面感染并引起人类咽炎(“链球菌咽炎”)，首先破坏呼吸道粘液的清除，然后附着在咽部细胞上。在分子水平上，这两个初始事件中的任何一个都没有特别好的理解。此外，人们对影响宿主对此类感染易感性的因素知之甚少。我们建议通过研究链球菌与人类之间最早的相互作用之一：与上呼吸道粘液(即唾液)的相互作用来解决这一差距。我们以前已经证明，在商业化的唾液粘蛋白(粘液凝胶的主要糖蛋白成分)制剂中，链球菌特异性地与单糖唾液酸结合，并且与唾液酸的结合在与咽上皮细胞的黏附中也是重要的。虽然上呼吸道粘液层是链球菌与其宿主最初相互作用的部位，但唾液粘液成分作为影响感染易感性的因素尚未被研究。作为这项应用的第一个目标，我们将测定对链球菌性咽炎易感性不同的儿童唾液样本中的唾液酸浓度，以确定感染率与唾液成分之间是否存在相关性。我们预测唾液酸浓度将在不同的易感人群中有所不同，并假设来自链球菌携带者或急性感染易感人群的唾液中唾液酸浓度将高于不易感人群。这一假说的提出是基于先前的发现，即覆盖在上呼吸道粘膜上的分泌型粘蛋白在结构上与底层组织表面暴露的糖蛋白相似。因此，唾液中唾液酸浓度的增加可能会反映咽部/扁桃体细胞上唾液酸化受体的数量增加，这种结合表位的增加将允许目标组织更有效地定植。由于感染是宿主和病原体之间的动态相互作用，研究链球菌如何感知并随后对不同的宿主环境做出反应也是很重要的。因此，作为第二个目标，我们建议检查与不同感染易感性儿童唾液样本接触时的转录调节和基因表达模式。有许多复杂的相互作用和许多潜在的生理因素将在发病机制中发挥作用，但对链球菌与不同儿童唾液相互作用过程中发生的特定分子事件知之甚少。我们预测，唾液介导的转录组将根据宿主的敏感性而不同。我们假设，与非携带者个体的唾液相比，与易感染儿童的唾液接触时，编码特定毒力决定因素的基因将上调。总体而言，这些研究可能为某些人比其他人更有可能患链球菌性咽炎的原因提供初步线索。 公共卫生相关性：关于链球菌性咽炎(“链球菌咽喉炎”)的一个长期存在的问题集中于为什么某些儿童比其他儿童更容易患上这种感染。我们的研究从一个新的角度解决这个问题，旨在确定：1)儿童唾液中唾液酸浓度的增加是否与急性咽炎或链球菌慢性定植的易感性增加相关；2)接触急性感染儿童的唾液是否会增加链球菌毒力基因的表达。据估计，全世界每年发生的咽炎病例超过6亿例，由于对这些感染治疗不当，目前有300万儿童患有风湿性心脏病，因此确定增加或降低儿童易感性的因素是一项紧迫的任务，如果要开发更好的预防疗法，就必须加以解决。