Immune Responses in Otitis Prone Children

易患中耳炎的儿童的免疫反应

• 批准号: 8418713
• 负责人: MICHAEL E PICHICHERO
• 金额: $ 52.92万
• 依托单位: ROCHESTER GENERAL HOSPITAL (NY)
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8418713
• 关键词: Acute; Adherence; Adopted; Antibiotic Therapy; Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; Automobile Driving; B-Lymphocytes; Bacteria; CD4 Positive T Lymphocytes; Cell physiology; Censuses; Child; Childhood; Clinical Research; Communicable Diseases; Cost Savings; Data; Defect; Development Plans; Diagnosis; Disease; Disease Progression; Drops; Epithelial; Epithelial Cells; Functional disorder; Funding; Future; Generations; Haemophilus Vaccines; Hearing; Helper-Inducer T-Lymphocyte; Immune; Immune response; Immunity; Immunologic Deficiency Syndromes; Immunologics; Infection; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Language Development; Lead; Mediator of activation protein; Methodology; Morbidity - disease rate; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Natural Immunity; Neonatal; Nontypable Haemophilus influenza; Nose; Otitis; Otitis Media; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Population; Preparation; Proteins; Publications; Recurrence; Research; Resistance; Respiratory Tract Infections; Role; Serum; Shapes; Speech Development; Streptococcus pneumoniae; T memory cell; T-Lymphocyte; Toll-like receptors; Tympanostomy; Up-Regulation; Vaccines; Viral; Viral Tumor Antigens; Virus; Virus Diseases; aged; cytokine; defined contribution; design; hearing impairment; immunogenicity; meetings; middle ear; pathogen; prospective; receptor; repository; respiratory; response; sample collection; time interval; trafficking; translational study; vaccine candidate; vaccine development

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.

描述（由申请人提供）： 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迟缓，甚至可能导致永久性听力损失。该项目寻求支持，继续我们对 AOM (RO1 DC 08671) 的前瞻性、纵向临床和转化研究，特别关注确定易患中耳炎 (OP) 儿童对不可分型流感嗜血杆菌 (NTHi) 和肺炎链球菌 (Spn) 感染引起的适应性和先天免疫反应缺陷。为了更好地了解 NTHi 和 Spn 发病机制并协助疫苗开发，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儿童粘膜免疫的独立贡献； (3) 了解先天反应对呼吸道细菌和病毒混合感染的作用； (4) 明确鼻咽 (NP) 炎症反应差异在塑造粘膜微环境以允许 NTHi/Spn 定植和感染中的作用。因此，我们将研究： 1. OP 与非 OP (NOP) 儿童相比，在 NP 定植和 AOM 后，导致对 NTHi 和 Spn 产生适应性免疫反应的能力减弱的机制。我们将定义导致免疫成熟度方面 T 细胞功能不良的机制，并检查生成记忆 T 细胞的能力，比较 NTHi/Spn 特异性 B 细胞的生成和活性，定义抗原呈递细胞功能的关键内在差异，并评估粘膜免疫反应。 2.先天免疫在并发病毒感染期间改变 NP 微环境以有利于 NTHi 和 Spn 定植，从而有助于 AOM 的发病机制。我们将确定先前呼吸道病毒感染期间 NP 的水平和中耳 NTHi/Spn 上皮粘附受体的上调；定义呼吸道病毒感染诱导的促炎细胞因子介质在改变 NTHi/Spn 定植抗性中的作用；并表征了 Toll 样受体 (TLR) 的表达作为 NTHi/Spn 定植的先天性和适应性免疫应答清除的介质。在我们当前的资助时间间隔内，我们重新定义了 OP 儿童表型，从而为这些儿童的研究提供了新的清晰度和方向。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道路。其次，我们将确定定植期间 NP 中“受控”炎症的关键介质，与导致疾病进展的病理性“不受控制”炎症相比，这些介质可促进有效的免疫反应。根据这些知识，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。