Disease severity of otitis media: Biofilms, invasion, and host responses

中耳炎的疾病严重程度：生物膜、侵袭和宿主反应

• 批准号: 8650970
• 负责人: Sheryl S Justice
• 金额: $ 36.63万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8650970
• 关键词: 15 year old; Abbreviations; Adult; Affect; Animal Model; Architecture; Attenuated; Cells; Chemicals; Child; Chinchilla (genus); Chronic; Clinical; Communicable Diseases; Communities; DNA Methylation; Data; Development; Diagnosis; Disease; Disease Outcome; Disease Progression; Elements; Environment; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Exhibits; Figs - dietary; Goals; Growth; Health; Height; Heme Iron; Human; Imagery; Immune; Immune response; Immunity; Individual; Infection; Inflammation Mediators; Inflammatory Response; Investigation; Iron; Kinetics; Lead; Life Style; Lower respiratory tract structure; Maintenance; Measures; Mediating; Microbial Biofilms; Modeling; Modification; Molecular; Monitor; Mucous Membrane; Nasopharynx; Nontypable Haemophilus influenza; Nutrient; Nutritional; Otitis Media; Pathogenesis; Pattern; Physiology; Positioning Attribute; Proteome; Publishing; Recurrence; Severities; Severity of illness; Site; Testing; Therapeutic Intervention; Time; Tissues; Variant; base; bone; combat; conditioning; cost; density; design; extracellular; fitness; genetic manipulation; hearing impairment; in vivo Model; insight; microorganism; middle ear; mutant; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pathogen; pressure; prevent; public health relevance; response; socioeconomics; therapeutic target; trafficking

ABSTRACT Otitis media (OM) is the most frequently diagnosed illness in children and a leading cause of hearing loss. OM and other diseases of the upper and lower respiratory tract caused by NTHI continue to be a significant health and socioeconomic problem in both children and adults. Despite this, we do not yet understand the dynamics of NTHI survival in the host, both as a commensal of the human nasopharynx and opportunistic pathogen of privileged anatomical sites (i.e. middle ear). Host sequestration of essential nutrients (termed nutritional immunity) serves to control bacterial growth, particularly in privileged sites. However, pathogens must overcome these barriers to growth to thrive and persist, ultimately causing disease. Our central hypothesis is that fluctuations in heme-iron availability influence the progression and severity of disease resulting in a microenvironment that potentiates NTHI persistence. Our long-term goal is to define therapeutic targets that will attenuate NTHI persistence, reduce tissue damage and diminish chronic sequelae. Here, our objective is to explore the consequence of fluctuations in essential heme-iron availability on NTHI physiology, biofilm development, invasion and disease severity. In our preliminary and published data we demonstrate that the severity of disease is directly related to the heme-iron status of NTHI at the time of introduction into the middle ear. We will test our central hypothesis through the following specific aims: 1) Determine the contribution of filamentation and DNA methylation on the biofilm developmental changes associated with fluctuations in heme-iron availability 2) Determine the contribution of heme-iron limitation on the duration and severity of OM sequelae (i.e. subclinical, symptomatic) and 3) Define the subcellular trafficking patterns of NTHI within middle ear epithelium as a consequence of heme-iron availability. We will further expand upon our novel models of symptomatic and subclinical OM to advance our understanding of the different manifestations of disease. Our investigations will increase our understanding of how NTHI adapts to nutritional limitation in the host, the influence of this adaptation on biofilm development and consequence on disease progression. In addition, the studies proposed will directly evaluate the potential utility of heme-iron sequestration through the use of agents to compete for iron on NTHI persistence to reduce the burden of NTHI-mediated OM. A better understanding of individual cell and NTHI community dynamics in the host and the microenvironmental changes that affect NTHI pathogenic lifestyles can be harnessed as potential novel therapeutics designed to ultimately thwart infectious disease states and thus significantly reduce the potential for recurrent infections and tissue damage that lead to adverse disease sequelae including hearing loss.

摘要 中耳炎(OM)是儿童最常见的诊断疾病，也是听力的主要原因 损失。由NTHI引起的OM和其他上下呼吸道疾病仍是一种 儿童和成人都面临严重的健康和社会经济问题。尽管如此，我们还没有 了解NTHI在宿主中存活的动力学，既作为人类鼻咽的共生体，也作为宿主的共生体 特殊解剖部位(如中耳)的机会性病原体。寄主对必需营养素的封存 (称为营养免疫)用于控制细菌生长，特别是在特权场所。然而， 病原体必须克服这些生长障碍才能茁壮成长并持续存在，最终导致疾病。我们的 中心假设是，可获得的血红素铁的波动影响疾病的进展和严重程度。 导致微环境增强了NTHI的持久性。我们的长期目标是定义治疗 将减弱NTHI持久性、减少组织损伤和减少慢性后遗症的靶点。在这里，我们的 目的：探讨必要的血红素铁供应波动对NTHI生理学的影响。 生物膜的发展、侵袭和疾病的严重性。在我们的初步和已发表的数据中，我们展示了 疾病的严重程度与NTHI在传入时的血红素铁状态直接相关 中耳。我们将通过以下具体目标来检验我们的中心假设：1)确定 丝状化和DNA甲基化在生物膜发育变化中的作用 血红素-铁有效性的波动2)决定了血红素-铁限制对持续时间和 OM后遗症的严重性(即亚临床、症状性)和3)定义了 中耳上皮中的NTHI是血红素铁供应的结果。我们将进一步扩大我们的 新的症状性和亚临床OM模型，以促进我们对不同表现的理解 疾病的威胁。我们的研究将增加我们对NTHI如何适应营养限制的理解 宿主，这种适应对生物膜发育的影响和对疾病进展的影响。在……里面 此外，拟议的研究将通过以下途径直接评估血红素铁封存的潜在效用 利用试剂竞争铁对NTHI的持久性，减轻NTHI介导的OM负担。更好的 了解寄主和微环境中单个细胞和NTHI群落的动态 影响NTHI致病生活方式的变化可以被利用为潜在的新疗法 最终阻止传染病状态，从而显著降低复发感染的可能性 以及导致包括听力损失在内的不良疾病后遗症的组织损伤。