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: 7938222
• 负责人: PATRICIA A RYAN
• 金额: $ 11.4万
• 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/7938222
• 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（由申请方提供）：A组链球菌通过上呼吸道粘膜表面感染，首先破坏呼吸道粘液的清除，然后附着在咽细胞上，从而引起人咽炎（“链球菌性咽喉炎”）。在分子水平上，这些初始事件中没有一个是特别好理解的。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来解决这一差距：与上呼吸道粘液（即唾液）的相互作用。我们以前已经表明，链球菌特异性结合的单糖，唾液酸，在市售制剂的唾液粘蛋白（粘液凝胶的主要糖蛋白成分），和唾液酸的结合也是重要的粘附咽上皮细胞。虽然上呼吸道粘液层是链球菌与其宿主之间最初相互作用的部位，但唾液粘液成分尚未被研究为影响感染易感性的因素。作为本申请的第一个目的，我们将确定来自对链球菌性咽炎表现出不同易感性的儿童的唾液样品中唾液酸的浓度，以确定感染率和唾液组成之间是否存在相关性。我们预测，唾液酸浓度将不同的易感群体之间，并假设唾液中的唾液酸浓度从个人谁是链球菌携带或急性感染易感将包含一个更高的浓度比非易感个体。这一假说的形成是基于先前的发现，即覆盖上呼吸道粘膜的分泌性粘蛋白在结构上与下层组织上的表面暴露的糖蛋白相似。因此，唾液粘液中唾液酸浓度的增加将可能反映咽/扁桃体细胞上唾液酸化受体数量的增加，并且结合表位的这种增加将允许靶组织的更有效定殖。由于感染是宿主和病原体之间的动态相互作用，因此研究链球菌如何感知并随后对不同的宿主环境作出反应也很重要。因此，作为第二个目标，我们建议检查的转录调控和基因表达模式在接触唾液样本从不同的感染易感性的儿童。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，但很少有人知道的具体分子事件，发生链球菌在与唾液粘液从不同的儿童。我们预测唾液介导的转录组将根据宿主易感性而不同。我们假设，与非携带者个体的唾液相比，在与感染易感儿童的唾液接触期间，编码特定毒力决定因子的基因将上调。总的来说，这些研究可能会为某些人比其他人更容易患链球菌性咽炎的原因提供初步线索。 公共卫生关系：关于链球菌性咽炎（“链球菌性咽喉炎”）的一个长期存在的问题集中在为什么特定的儿童比其他儿童更容易发生这种感染的原因上。我们的研究从一个新的角度解决了这个问题，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有关，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，全世界每年发生超过6亿例咽炎，目前有300万儿童因这些感染的治疗不当而患有风湿性心脏病，因此，确定增加或减少儿童易感性的因素是一个紧迫的问题，如果要开发更好的预防疗法，就必须解决这个问题。