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: 8915375
• 负责人: Sheryl S Justice
• 金额: $ 7万
• 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/8915375
• 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; response; socioeconomics; therapeutic target; trafficking

DESCRIPTION (provided by applicant): 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.

描述(由申请人提供)：中耳炎(OM)是儿童中最常见的诊断疾病，也是导致听力损失的主要原因。由NTHI引起的OM和其他上呼吸道和下呼吸道疾病仍然是儿童和成人的重大健康和社会经济问题。尽管如此，我们还不清楚NTHI在宿主中的存活动力学，既是人类鼻咽的共生，也是特殊解剖部位(即中耳)的机会性病原体。宿主对必需营养素的隔离(称为营养免疫)用于控制细菌的生长，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，血红素铁供应的波动影响疾病的进展和严重程度，导致微环境加强NTHI的持久性。我们的长期目标是确定治疗目标，以减轻NTHI的持久性，减少组织损伤和减少慢性后遗症。在这里，我们的目标是探索必要的血红素铁供应的波动对NTHI生理、生物膜发育、侵袭性和疾病严重性的影响。在我们的初步和已发表的数据中，我们证明了疾病的严重程度与NTHI在进入中耳时的血红素铁状态直接相关。我们将检验我们的中心假设 通过以下具体目标：1)确定丝状化和DNA甲基化对与血红素铁有效性波动相关的生物膜发育变化的贡献；2)确定血红素铁限制对OM后遗症(即亚临床的、症状性的)持续时间和严重程度的贡献；3)确定由于血红素铁的有效性，NTHI在中耳上皮内的亚细胞运输模式。我们将进一步扩展我们的症状和亚临床OM的新模型，以促进我们对疾病的不同表现的理解。我们的研究将增加我们对NTHI如何适应宿主的营养限制、这种适应对生物膜发育的影响以及对疾病进展的影响的理解。此外，建议的研究将直接评估通过使用试剂在NTHI持久性上竞争铁来减轻NTHI介导的OM负担的血红素-铁隔离的潜在效用。更好地了解宿主中的个体细胞和NTHI群落动态以及影响NTHI致病生活方式的微环境变化可以被用作潜在的新疗法，旨在最终阻止传染病状态，从而显著降低导致包括听力损失在内的不良疾病后遗症的复发感染和组织损伤的可能性。