Pathogenesis of virus-induced acute otitis media

描述(由研究人员提供)：中耳炎(OM)是儿科实践中最常见的疾病，被认为是一种具有复杂和相互关联的遗传、环境和感染病因的多因素疾病。我们研究组的长期目标是阐明感染性病原体的作用，以及它们与其他OM危险因素在急性中耳炎(AOM)的发病和康复中的复杂相互作用，并确定更有效的预防和/或治疗的可能策略。我们最近发现促炎性细胞因子基因(TNF1-308和IL-6-174)的多态与OM易感性的增加有关，以及环境因素如母乳喂养(BF)和吸烟暴露(CSE)对多态个体OM易感性的可能的调节作用。在下一个资助期间，我们建议进一步研究病毒诱导性肺炎的发病机制，特别是研究遗传风险因素(以TNF1-308和IL-6-174基因多态为代表)导致宿主OM易感的机制，以及环境因素是否可以改变遗传易感性儿童的OM风险。目的1：对300名具有和不具有TNF1-308基因多态的婴儿进行前瞻性病例对照研究，随访至1岁以下的首次AOM发病。受试者将接受基因多态筛查；相同数量的多态和正常婴儿(性别和种族匹配)将在出生后第一个月内加入研究。前6个月鼻咽部细菌定植动态。将对生命的影响进行研究；将监测有症状的URI发作是否有AOM并发症。关于BF、CSE和DC出席率的信息将被前瞻性地收集并持续更新。将在多形性和正常儿童组之间比较出生第一年的AOM发病率(第一年至少有一次发作的病例的百分比)；将评估环境风险因素对细菌定植、病毒性URI和AOM的影响。样本量也将足以平行比较IL-6-174基因多态儿童和正常儿童。目的：进一步探讨其他几种细胞因子/趋化因子基因多态性与OM易感性的关系。来自拟议研究1的存档和新的DNA样本(来自多发性硬化症易感和非多发性硬化症儿童，n=800)将使用最先进的微阵列技术测试11个细胞因子/趋化因子基因多态。基因多态将与OM易感性相关；数据挖掘将被用于分析复杂的数据。我们的研究产生的信息将对公共卫生很重要，因为它将为设计预防多发性硬化症的创新方法奠定基础，特别是在天生具有遗传易感性和暴露于多发性硬化症环境风险的儿童中。公共卫生相关性中耳炎是一种在婴儿和儿童中高度流行的疾病。这项研究与公共卫生有关，因为将产生的信息将成为设计预防中耳炎的创新方法的基础，特别是在天生具有遗传易感性和暴露于OM环境风险的儿童中。

DESCRIPTION (provided by investigator): Otitis media (OM) is the most common disease seen in pediatric practice and is recognized as a multifactorial disease with complex and interrelated genetic, environmental and infectious etiologies. The long- term objectives of our research group are to elucidate the contribution of infectious pathogens, and their complex interactions with other OM risk factors in the pathogenesis of and recovery from acute otitis media (AOM), and to identify possible strategies for more effective prevention and/or treatment. We have recently found an important association between proinflammatory cytokine gene polymorphisms (TNF1-308 and IL- 6-174) and increased OM susceptibility, and possible modifying effects of environmental factors such as breastfeeding (BF) and cigarette smoke exposure (CSE) on OM susceptibility in polymorphic individuals. During the next funding period, we propose to study further the pathogenesis of virus-induced AOM, specifically on the mechanisms by which genetic risk factors (as represented by TNF1-308 and IL- 6-174 polymorphisms) render the host OM susceptible and whether environmental factors could modify OM risks in children with genetic predisposition. Aim 1: Perform a prospective, case-control study of 300 infants with and without TNF1-308 polymorphism followed to the first AOM episode up to 1 year of age. Subjects will be screened for the gene polymorphism; equal number of polymorphic and normal infants (matched for gender and race) will be enrolled into the study within the first month of life. The dynamics of nasopharyngeal bacterial colonization in the first 6 mos. of life will be studied; symptomatic URI episodes will be monitored for AOM complication. Information on BF, CSE, and DC attendance will be collected prospectively and updated continuously. Incidence of AOM in the first year of life (per cent of cases with at least one episode in the first year) will be compared between polymorphic and normal children groups; modifying effects of environmental risk factors on bacterial colonization, incidence of viral URI and AOM will be assessed. Sample size will also be adequate for parallel comparison between IL- 6-174 polymorphic and normal children. Aim 2: Investigate further the association between several other cytokine/ chemokine gene polymorphisms and OM susceptibility. Archived and new DNA samples from the proposed Study 1 (from OM-susceptible and non-OM susceptible children, n=800) will be tested for 11 cytokine/ chemokine gene polymorphisms using the state-of-the-art microarray technique. Gene polymorphisms will be associated with OM susceptibility; data mining will be used to analyze complex data. Information generated from our studies will be important to public health as it will lay the ground work for the design of innovative approaches to prevent OM, especially in children born with genetic predisposition and those exposed to OM environmental risks. PUBLIC HEALTH RELEVANCE Otitis media is a highly prevalent disease in infants and children. This study is relevant to public health because information to be generated will be the basis for the design of innovative approaches to prevent otitis media, especially in children born with genetic predisposition and those exposed to OM environmental risks.