Endogenous Adjuvants in Viral Immunity and Vaccines

项目1的主题是一类新型佐剂的表征，基于我们的发现，哺乳动物细胞包含具有独特佐剂属性的分子，当细胞受到损伤时会释放这些分子，并向免疫系统发出危险警报。我们的基本假设是，这些内源性分子通常在启动对感染的免疫反应中发挥重要作用，可以作为一类新的疫苗佐剂来开发。这个项目的目标是建立这些分子的分子鉴定，阐明它们的生物学效应和潜在的作用机制，并 测试它们对A类生物防御病原体LCMV疫苗的潜在效用。这些研究的一个重要方面将是我们与#2和#3项目的互动，以检查内源性佐剂是否通过Toll样受体(TLR)起作用，和/或各种TLR激动剂是否与内源性佐剂的刺激协同作用。这个项目由三个目标组成。第一个目标是提纯主要的内源性佐剂并确定其分子结构。第二个目标将阐明它们增强的免疫反应的种类，确定它们与TLR激动剂的比较，并评估这些分子作为疫苗佐剂单独或联合使用是否有用。这个目标的重要性在于它将 确定这些佐剂有助于调节哪种免疫反应，从而确定它们将在什么环境下对提高疫苗效力有用。第三个目标将阐明内源性佐剂活性的细胞和分子机制。我们将检验这一假说，即它们通过作用于树突状细胞来增强免疫反应，并定义树突状细胞功能(或其他细胞靶点)是如何改变的。我们还将测试这些佐剂分子通过TLRs发出信号的假设。此外，我们还将比较内源性佐剂和TLRs微生物激动剂引起的分子变化。将这些目标和其他项目的目标结合在一起将提供洞察力 研究感染LCMV如何导致免疫对抗疾病，并确定用于疫苗开发的新型佐剂类别。

The theme of project 1 is the characterization of a novel class of adjuvants and is based on our discovery that mammalian cells contain molecules with unique adjuvant properties that are released when cells are injured and alert the immune system to danger. Our underlying hypothesis is that these endogenous molecules normally play an important role in initiating immune responses to infections and can be exploited as a novel class of adjuvants for vaccines. The objectives of this project are to establish the molecular identify of these molecules, to elucidate their biological effects and underlying mechanisms of action, and to test their potential utility for vaccines for the class A biodefense pathogen, LCMV. An important aspect of these studies will be our interaction with projects #2 and #3 to examine whether the endogeous adjuvant works through Toll-like receptors (TLR) and/or whether various TLR agonists synergize with stimulation by the endogenous adjuvants. This project consists of three Aims. The first Aim will purify the major endogenous adjuvants and determine their molecular structure. The second Aim will elucidate the kinds of immune responses they enhance, determine how they compare to TLR agonists and evaluate whether these molecules are useful alone or in combination as vaccine adjuvants. The importance of this goal is that it will define what kinds of immune responses these adjuvants help to regulate and hence the settings in which they will be useful for enhancing vaccine efficacy. The third aim will elucidate the cellular and molecular mechanisms of the endogenous adjuvant activity. We will examine the hypothesis that they augment immune responses by acting on dendritic cells and define how dendritic cell function (or that of other cellular targets) is changed. We will also test the hypothesis that these adjuvant molecules signal through TLRs. In addition, we will compare the molecular changes induced by the endogenous adjuvants to those stimulated by microbial agonists of TLRs. Together these Aims and the ones of the other projects will provide insight into how infection with LCMV leads to immunity versus disease and identify novel classes of adjuvants for vaccine development.