Competition Among Bacterial Resiratory Pathogens

描述（由申请人提供）：急性呼吸道感染（ARI）是发病率和死亡率的主要原因。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的流感嗜血杆菌（NTHi）。它们共同的生态位鼻咽部的定植在这两个物种中都非常普遍，这是它们发病机制的第一步。最近的临床数据表明，疫苗接种导致一种细菌携带减少，可能会加剧由另一种细菌引起的疾病。这一观察结果，以及证实这些物种在体外和动物定植模型中竞争的初步数据，构成了该应用程序确定肺炎链球菌和NTHi之间竞争的具体机制的基本原理。该方法将侧重于在其发病机制中共同的主题。这两种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，但使生物对c反应蛋白（CRP）介导的先天免疫敏感。此外，由肺炎链球菌表达的一种神经氨酸酶可以使宿主受体和唾液化的流感嗜血杆菌LPS失活。涉及细菌磷胆碱和神经氨酸酶作用的竞争将在三个高度探索性的特定目标中进行分析。目的1将检验一个假设，即存在直接的细菌-细菌相互作用，导致它们在共同的生态位（鼻咽粘膜表面）竞争。肺炎球菌神经氨酸酶对栗鼠鼻咽部定植和竞争（包括体外胆碱获取）模型NTHi的影响将被确定。目的2研究细菌与呼吸道上皮细胞的相互作用是否通过rPAF或宿主受体的去脂酰化促进粘附性的竞争。目的3探讨宿主的上皮细胞炎症反应和TNFa和CRP的细化是否有利于一种物种的粘附和/或定植。获得的信息将有助于长期努力了解这些重要病原体在其共同生态位中竞争的分子机制。通过减少携带来减少疾病负担的未来战略可能源于对物种之间相互作用的更深入了解。

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.