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

描述（由申请人提供）：中耳炎（OM）是儿童中最常见的疾病，也是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一个重大健康和社会经济问题。尽管如此，我们还不了解NTHI在宿主中的生存动态，无论是作为人类鼻咽部的共生体还是特权解剖部位（即中耳）的机会性病原体。宿主对必需营养物质的隔离（称为营养免疫）有助于控制细菌生长，特别是在特权部位。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可用性的波动影响疾病的进展和严重程度，导致微环境增强NTHI的持久性。我们的长期目标是确定治疗靶点，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，我们的目的是探讨必需血红素铁可用性波动对NTHI生理、生物膜发育、侵袭和疾病严重程度的影响。在我们的初步和发表的数据中，我们证明了疾病的严重程度与NTHI在引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

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.