Immune Responses in Otitis Prone Children

描述(申请人提供)：急性中耳炎(AOM)是儿童中最常见的传染病。在AOM期间，儿童的听力通常会下降，这可能会导致暂时的言语和语言发育延迟，并可能导致永久性的听力损失。该项目寻求支持，以继续我们的前瞻性、纵向临床和翻译研究(RO1 DC 08671)，特别关注确定易中耳炎(OP)儿童对非分型流感嗜血杆菌(NTHI)和肺炎链球菌(Spn)感染的适应性和先天免疫反应缺陷。为了更好地了解NTHi和Spn的发病机制并帮助疫苗开发，我们计划(1)确定OP儿童中特定的适应性免疫缺陷；(2)确定OP儿童黏膜免疫的独立贡献；(3)了解呼吸道细菌和病毒混合感染的先天性反应所起的作用；以及(4)确定鼻咽(NP)炎症反应中的差异在塑造黏膜微环境中的作用，以允许NTHi/Spn定植并随后感染。因此，我们将研究：1.OP和非OP(NOP)儿童在NP定植和AOM后对NTHi和Spn产生适应性免疫反应的能力降低的机制。我们将根据免疫成熟度确定导致T细胞功能低下的机制，并检查产生记忆T细胞的能力，比较NTHi/Spn特异性B细胞的生成和活性，确定抗原提呈细胞功能的关键内在差异，并评估粘膜免疫反应。2.在并发病毒感染时，先天免疫改变NP微环境有利于NTHi和Spn定植，从而有助于AOM的发病。我们将确定在既往呼吸道病毒感染过程中NTHi/Spn上皮黏附受体的NP水平和中耳上调；确定呼吸道病毒感染诱导的促炎细胞因子介质在改变对NTHi/Spn定植抵抗中的作用；以及Toll样受体(TLR)的表达作为NTHi/Spn定植的先天和获得性免疫反应清除的介体。在我们目前的资助时间间隔内，我们重新定义了OP儿童的表型，从而为这些儿童的研究提供了新的清晰和方向。进一步了解OP儿童的免疫缺陷，将为未来候选疫苗的合理设计指明方向。其次，我们将在NP的定植期间建立“受控”炎症的关键介质，与允许疾病进展的病理性“非受控”炎症相比，这些介质促进有效的免疫反应。根据这一知识，我们可以寻求调节或沉默那些促进疾病进展的先天免疫反应途径，同时保留促进保护性免疫原性的必要先天反应。

DESCRIPTION (provided by applicant): Acute Otitis Media (AOM) is the most common infectious disease among children. During AOM, children typically have diminished hearing and this can lead to temporary delayed speech and language development and possibly permanent hearing loss. This project seeks support to continue our prospective, longitudinal clinical and translational studies of AOM (RO1 DC 08671) with a specific focus on defining the adaptive and innate immune response deficits among otitis prone (OP) children to infections caused by nontypeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae (Spn). To better understand NTHi and Spn pathogenesis and assist in vaccine development we plan to (1) identify specific adaptive immune deficits in OP children; (2) determine independent contributions of mucosal immunity in OP children; (3) understand the role of innate responses to co-infection of respiratory bacteria and viruses; and (4) define the role of differences in the nasopharyngeal (NP) inflammatory response in shaping the mucosal microenvironment to allow for NTHi/ Spn colonization and then infection. Therefore, we will investigate: 1. The mechanisms causing a diminished capacity to generate adaptive immune responses to NTHi and Spn following NP colonization and AOM in OP versus non-OP (NOP) children. We will define mechanisms causing poor T-cell function with respect to immune maturity and examine the capacity to generate memory T-cells, compare the generation and activity of NTHi/Spn specific B-cells, define key intrinsic differences of antigen-presenting cell function and evaluate mucosal immune responses. 2. The contributions of innate immunity that alters the NP microenvironment to favor NTHi and Spn colonization during concurrent viral infections to aid the pathogenesis of AOM. We will determine the level of NP and middle ear up-regulation of NTHi/Spn epithelial adherence receptors during antecedent respiratory viral infections; define the role of pro-inflammatory cytokine mediators induced by respiratory viral infections in modifying resistance to NTHi/Spn colonization; and characterize expression of toll like receptors (TLR) as mediators of innate and adaptive immune response clearance of NTHi/Spn colonization. During our current funding time interval, we have re-defined the OP child phenotype thereby providing new clarity and direction in the study of these children. Further understanding immune defects in OP children, will point the way to rational design of future candidate vaccines. Second, we will establish the key mediators of "controlled" inflammation in the NP during colonization that promote an effective immune response compared to pathological "uncontrolled" inflammation that allows disease progression. From that knowledge we can seek to modulate or silence those innate immune response pathways that facilitate disease progression while preserving the necessary innate responses that facilitate protective immunogenicity.