Quantitative Determination of Ecological Niches for Polymicrobial Colonization in

描述(由申请人提供)：定量测定多菌在中耳炎(OM)中定植的生态位是一种常见的儿科疾病，通常由无菌中耳由通常存在于上呼吸道(URT)的共生细菌感染引起。OM为研究宿主-微生物区系相互作用的基本机制提供了一种独特而简单的范式，其中共生细菌、非分型流感嗜血杆菌(NTHI)、肺炎链球菌(Sp)和卡他分枝杆菌(Mcat)与宿主免疫系统之间的稳态被病毒感染(如RSV或A型流感)破坏可导致疾病状态。破坏共生细菌和宿主之间的动态平衡的机制还不是很清楚。跨越广泛的空间维度(分子到器官水平)和时间尺度(几秒到几天)的多个非线性相互关联的过程决定了OM涉及的主要参与者(细菌、病毒、免疫反应)之间的相互作用。因此，仅仅通过实验很难破译潜在的机制。我们建议使用基于统计物理学、非线性种群动力学和统计学的计算工具的协同组合，并结合龙猫城市轨道交通的湿实验，来确定和量化OM中多微生物感染/定植城市轨道交通的生态位。在具体目标1中，我们将定量地确定NTHI、Sp和Mcat感染龙猫中耳的生态位。在目标2中，我们将确定龙猫URT中一种病毒和一种共生细菌之间可能导致细菌物种感染中耳的潜在机制，最后，我们将确定Mcat和NTHI在协同病毒感染时导致中耳多物种感染的机制。

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.