TLR and Notch Ligand in RSV-induced Disease

婴儿呼吸道病毒感染可对呼吸道产生严重的破坏性影响 功能，但也可能影响儿童和儿童的长期肺功能 成年人。最常见的呼吸道感染是导致 儿童住院(90%)是呼吸道合胞病毒(RSV)感染。这个 启动适当的抗病毒反应是成功清除该病毒的强制性条件 具有最小病理生理反应的病原体。在本提案中，我们将重点关注 关于RSV感染的最早免疫反应涉及Toll-1的初始激活 树突状细胞(DC)上的类受体(TLR)与重要的 启动获得性免疫反应的指示信号。最近的研究结果表明 证实缺口/缺口配体诱导的激活在激活过程中起着重要作用 成熟T细胞的分化。树突状细胞表面特异性缺口配体的上调 依赖于MyD88，是成熟T细胞分化的关键步骤。 然而，对Notch/Notch配体激活通路在血管内皮细胞中的作用知之甚少 在病毒感染期间产生有效的免疫反应。我们的假设是 这一命题是TLR介导的缺口配体Delta-like 4是需要的 启动适当的免疫反应，在没有RSV感染的情况下 变得更具致病性，并导致免疫环境改变。这些 研究将通过取得进展，具体解决几个新的机械问题 通过3个特定目标：1)确定TLR诱导的DC的关键激活 RSV感染过程中的抗病毒信号通路；2)确定Delta-2的作用。 类4在RSV诱导的免疫反应和肺部病理发展中的作用； 3)确定浆细胞样树突状细胞与传统树突状细胞在 呼吸道合胞病毒感染与T细胞活化及Delta-like 4表达的关系把这些放在一起 个人的特定目标，这些目标彼此独立，但又清楚地结合在一起，将 每一种都解决了我们的总体假设。我们将对这些观察结果进行调查 在基因敲除小鼠中机械地结合研究，特异性地 中和抗体和细胞转移实验以及DC和T淋巴细胞 与世隔绝。使用特定的新型试剂和先进的技术将使我们的 高度集成的调查小组，专门针对这些机制 符合逻辑的翻译方式。

Respiratory viral infections in infants can have devastating effects acutely on airway function, but may also impact the longterm function of the lung in both children and adults. The most common respiratory infection that is the predominant cause of hospitalization in children (>90%) is respiratory syncytial virus (RSV) infection. The initiation of the proper anti-viral responses are mandatory for successfully clearing this pathogen with minimal pathophysiologic responses. In the present proposal we will focus on the earliest immune responses to RSV infection involving the initial activation of toll- like receptors (TLRs) on dendritic cells (DCs) followed by the upregulation of important instructive signals that initiate the acquired immune responses. Recent findings have identified that notch/notch ligand induced activation has a profound role on the activation and differentiation of mature T cells. The upregulation of specific notch ligands on DCs is MyD88-dependent and provides a critical step in mature T cell differentiation. However, little is known about the role of Notch/notch ligand activation pathways for the generation of effective immune responses during virus infections. Our hypothesis for this proprosal is that TLR-mediated notch ligand delta-like 4 is required for the initiation of the appropriate immune response, and without it RSV infection becomes more pathogenic and results in an altered immune environment. These studies will specifically address several novel mechanistic questions by progressing through 3 specific aims that will 1) determine the critical TLR-induced DC activation pathway during RSV infection for anti-viral instructive signals; 2) identify the role of delta- like 4 in the development of RSV-induced immune responses and pulmonary pathology; 3) determine the differential role of plasmacytoid versus conventional DC populations for the expression of delta-like 4 and T cell activation in RSV infection. Together these individual specific aims, which are independent of one another yet clearly integrated, will each address our overall hypothesis. We will investigate these observations mechanistically using a combination of studies in gene knockout mice, specific neutralizing antibodies, and cell transfer experiments along with DC and T lymphocyte isolation. The use of specific novel reagents and advanced techniques will allow our highly integrated group of investigators to specifically target these mechanisms in a logical translational manner.