Competition Among Bacterial Resiratory Pathogens

描述（由申请方提供）：急性呼吸道感染（ARI）是发病和死亡的主要原因。该应用程序侧重于ARI的两个最突出的原因，肺炎链球菌和不可分型流感嗜血杆菌（NTHi）。它们共同的生态位-鼻咽的定植对于这两个物种来说都是非常常见的，并且代表了它们发病机制的第一步。最近的临床数据表明，疫苗接种导致一个物种的携带减少，可能会加剧另一个物种引起的疾病。这一观察结果，以及初步数据证实，这些物种在体外竞争，并在动物模型中的殖民，形成的基本原理，本申请，以确定具体的竞争机制之间的S。pneumoniae和NTHi。该方法将侧重于其发病机制中常见的主题。两种微生物都表达细胞表面磷酸胆碱（ChoP），这是一种不寻常的细菌结构，允许与表达血小板活化因子（rPAF）受体的上皮细胞结合，但使微生物对C反应蛋白（CRP）介导的先天免疫敏感。此外，还对S. pneumoniae可使宿主受体和H.流感。竞争涉及细菌磷酸胆碱和神经氨酸酶的影响将在三个高度探索性的具体目标进行分析。目的1将测试的假设，有直接的细菌-细菌相互作用，导致竞争的共同生态位，粘膜表面的鼻咽。将确定肺炎球菌神经氨酸酶对体外涉及胆碱获取的鼻咽定殖和竞争的栗鼠模型中NTHi的影响。目的2检查细菌与呼吸道上皮细胞的相互作用是否促进粘附竞争，包括通过rPAF或通过宿主受体的去唾液酸化结合。目的3探索宿主的上皮细胞炎症反应和TNFa和CRP的产生是否有利于一个物种的粘附和/或定殖。所获得的信息将有助于更长期的努力，以了解这些重要的病原体在其共同的生态位之间的竞争的分子机制。通过减少携带来减少疾病负担的未来战略可能来自于对物种之间相互作用的更好理解。

DESCRIPTION (provided by applicant): Acute respiratory infection (ARI) is a major cause of morbidity and mortality. This application focuses on two of the most prominent causes of ARI, Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi). Colonization of their common niche, the nasopharynx, is extremely common for both species and represents the first step in their pathogenesis. Recent clinical data suggests that vaccination resulting in reduced carriage of one species may exacerbate disease caused by the other. This observation, together with preliminary data confirming that these species compete in vitro and in animal models of colonization, form the rationale for this application to determine the specific mechanisms of competition between S. pneumoniae and NTHi. The approach will focus on themes that are common in their pathogenesis. Both organisms express cell-surface phosphorylcholine (ChoP), an unusual bacterial structure that allows for binding to epithelial cells expressing the receptor for platelet activating factor (rPAF) but renders the organisms sensitive to innate immunity mediated by C-reactive protein (CRP). In addition, a neuraminidase expressed by S. pneumoniae can desialylate host receptors and the sialylated LPS of H. influenzae. Competition involving bacterial phosphorylcholine and the effects of neuraminidase will be analyzed in three highly exploratory specific aims. Aim 1 will test the hypothesis that there is direct bacterial-bacterial interaction that results in competition in their common niche, the mucosal surface of the nasopharynx. The effect of pneumococcal neuraminidase on NTHi in a chinchilla model of nasopharyngeal colonization and competition involving choline acquisition in vitro will be determined. Aim 2 examines whether bacterial interactions with respiratory tract epithelial cells promote competition in adherence involving binding via the rPAF or by desialylation of host receptors. Aim 3 explores whether the host's epithelial cell inflammatory response and the elaboration of TNFa and CRP favor adherence and/or colonization of one species over the other. The information obtained will facilitate a longer-term effort to understand the molecular mechanisms for competition between these important pathogens in their common niche. Future strategies to decrease disease burden by reducing carriage could result from a greater understanding of interactions between species.