Pathogenesis of Virus-Induced Acute Otitis Media

描述(由申请人提供)：中耳炎(OM)是最常见的儿科疾病，被认为是多因素的，具有复杂的遗传、环境和感染性病因。急性中耳炎(AOM)通常是儿童病毒性上呼吸道感染(URI)的细菌性并发症。有证据表明，不同类型的病毒诱发AOM的能力不同。我们研究组的长期目标是阐明病毒、细菌及其复杂的相互作用在AOM的发病机制和康复中的作用，并确定更有效的预防和/或治疗的可能策略。这项为期5年的研究将调查“宿主”和“微生物”在病毒诱导的AOM发展过程中的关系。我们将探讨特定呼吸道病毒的致病性，以及促炎细胞因子(TNFcx、IL-1B、IL-6)及其基因调控在病毒诱导AOM机制中的作用。在目标1中，我们将研究病毒诱导的AOM在体内和体外的差异细胞因子的表达。我们将前瞻性跟踪210名婴儿和儿童，有和没有急性期细胞因子基因(TNFcx(-308，IB-+3953和IL-6等位基因))的多态性，为期一年。在每次病毒URI发作后的3周内，我们将监测AOM的发生。我们将比较AOM患者和非AOM患者呼吸道分泌物中的病毒类型和细胞因子浓度。将评估AOM发生的风险与细胞因子基因型别的关系。在体外实验中，将研究特定病毒对具有正常或多态细胞因子基因的健康成年志愿者外周血单核白细胞产生细胞因子的诱导作用。目的采用200例有和无复发性OM病史的儿童外周血，回顾分析促炎性细胞因子基因多态性与OM易感性之间的关系。这些研究将阐明特定的呼吸道病毒、促炎细胞因子及其基因调控在病毒诱导的AOM发病机制中的作用。研究结果应该会改善人群中复发OM的风险识别，这可能有助于高危人群的特定预防和治疗方法。这项研究还将为未来设计预防或减少AOM发病率的创新方法奠定基础，例如使用特定靶向病毒疫苗、抗病毒药物和免疫调节剂的治疗。

DESCRIPTION (provided by applicant): Otitis media (OM), the most common pediatric disease, is recognized to be multifactorial, with complex genetic, environmental and infectious etiologies. Acute otitis media (AOM) usually occurs as a bacterial complication of viral upper respiratory tract infection (URI) in children. Evidence suggests that different types of viruses vary in their ability to induce AOM. The long-term objectives of our research group are to elucidate the contribution of viruses, bacteria and their complex interactions in the pathogenesis of and recovery from AOM, and to identify possible strategies for more effective prevention and/or treatment. The proposed 5-year study will investigate the relationship between "host" and "microbe" in the development of virus-induced AOM. We will explore the pathogenicity of specific respiratory viruses, and the role of proinflammatory cytokines (TNFcx, -IL-1B, IL-6) and their gene regulation in the mechanisms of virus-induced AOM. In Aim 1, we will study differential cytokine expression in virus-induced AOM in vivo and in vitro. We will prospectively follow 210 infants and children, with and without polymorphisms of acute phase cytokine genes (TNFcx(-308, IB-+3953, and IL- 6 alleles) for one year. For 3 weeks after each viral URI episode, we will monitor for the occurrence of AOM. We will compare virus type and cytokine concentrations in respiratory secretions from children who do and who do not develop AOM as a complication. Risk for AOM development will be evaluated for association with cytokine genotypes. In the in vitro experiments, induction of cytokine production by specific viruses will be studied in peripheral blood mononuclear leukocytes from healthy adult volunteers with normal or polymorphic cytokine genes. Aim 2 will retrospectively evaluate the association between polymorphisms of proinflammatory cytokine genes and susceptibility to OM, using peripheral blood from 200 children with and without a history of recurrent OM. These studies will clarify the role of specific respiratory viruses, proinflammatory cytokines, and their gene regulation in the pathogenetic mechanisms of virus-induced AOM. Study results should improve risk identification for recurrent OM in the population, which may facilitate specific prophylactic and therapeutic approaches for the high risk groups. The study will also lay the ground work for the future design of innovative approaches to prevent or reduce morbidity of AOM, such as therapies using specifically targeted viral vaccines, antiviral drugs, and immunomodulators.