Quantitative Determination of Ecological Niches for Polymicrobial Colonization in

描述（由申请方提供）：OM中多种微生物定植的生态位的定量测定中耳炎（OM）是一种常见的儿科疾病，通常由通常存在于上呼吸道（URT）中的细菌对无菌中耳的多种微生物感染引起。OM为研究宿主-微生物群相互作用的基本机制提供了一个独特而简单的范例，其中一个小的肠道细菌群落，不可分型的H。流感（NTHI）、S. pneumoniae（Sp）和M.粘膜炎（Mcat）和宿主的免疫系统被病毒感染（如RSV或甲型流感）可导致疾病状态。体内细菌和宿主之间的内环境平衡被破坏的机制还没有很好的理解。跨越广泛的空间维度（分子到器官水平）和时间尺度（秒到天）的多个非线性互连过程决定了参与OM的主要参与者（细菌，病毒，免疫反应）之间的相互作用。因此，仅通过实验很难破译潜在的机制。我们建议使用一个协同组合的计算工具植根于统计物理学，非线性种群动力学和统计学，在龙猫URT湿实验，以确定和量化生态位的基础上多微生物感染/殖民化的URT OM。在具体的目标1，我们将定量确定生态位感染的灰鼠中耳NTHI，SP，和Mcat。在目标2中，我们将确定一种病毒和一种类型的真菌细菌之间的协同作用的机制，在灰鼠URT，可能导致中耳感染的细菌物种，并在最后一个目标，我们将确定机制，导致多物种感染的中耳Mcat和NTHI后，协同病毒感染。

DESCRIPTION (provided by applicant): Quantitative determination of ecological niches for polymicrobial colonization in OM Otitis media (OM) is a common pediatric disease usually caused by polymicrobial infection of the sterile middle ear by commensal bacteria that normally reside in the upper respiratory tract (URT). OM presents a unique and simple paradigm for studying basic mechanisms of host-microbiota interactions, where breakdown of homeostasis between a small community of commensal bacteria, nontypeable H. influenzae (NTHI), S. pneumoniae (Sp), and, M. catarrhalis (Mcat), and the host's immune system by a viral infection (such as RSV or influenza A) can lead to a diseased state. The mechanisms that underlie breakdown of the homeostasis between commensal bacteria and the host are not well understood. Multiple nonlinear interlinked processes spanning a wide range of spatial dimensions (molecular to organ level) and time scales (seconds to days) determine interactions between the main players (bacteria, viruses, immune responses) involved in OM. Therefore, it is difficult to decipher the underlying mechanisms solely through experiments. We propose to use a synergistic combination of computational tools rooted in statistical physics, non-linear population dynamics, and statistics, with wet experiments in the chinchilla URT to determine and quantify ecological niches that underlie polymicrobial infection/colonization of the URT in OM. In specific aim 1, we will quantitatively determine ecological niches for infection of the chinchilla middle ear by NTHI, Sp, and Mcat. In aim 2, we will determine mechanisms underlying synergy between one virus and one type of commensal bacteria in the chinchilla URT that could lead to infection of the middle ear by the bacterial species, and in the last aim, we will determine mechanisms that lead to multispecies infection of the middle ear by Mcat and NTHI upon a synergistic viral infection.