NAD and CD38: modulators of inflammation and immunity

描述（由申请人提供）：流感病毒感染在美国和世界范围内引起显著的发病率和死亡率。由于目前的灭活病毒疫苗不能对新出现的流感病毒株产生保护性免疫，因此迫切需要新的疫苗。不幸的是，目前的灭活病毒疫苗不含佐剂，也不能诱导持久的细胞免疫。由于唯一被批准用于人类的佐剂是明矾，而明矾可增强通常对肺功能有害的2型免疫反应，因此确定可用于流感疫苗的新型安全佐剂非常重要。最常用的实验性佐剂是病原体衍生的，通过触发toll样受体（tlr）来增强免疫反应，从而诱导炎症和组织损伤并激活树突状细胞。然而，与tlr无关的其他分子也有可能调节免疫反应。其中一个分子是外酶CD38，它分解细胞外NAD，由受损和死亡细胞释放，产生Ca2+动员代谢产物，调节趋化因子受体信号。CD38及其底物NAD是白细胞迁移所必需的，对功能性效应T细胞的产生也很重要。有趣的是，当NAD与蛋白抗原和亚阈值佐剂共同施用时，可显著增强T细胞依赖性免疫反应。基于这些数据，我们假设NAD作为一种“协同佐剂”来增强先天和适应性免疫反应，CD38和细胞外NAD代表了一类不同于tlr的新型免疫调节剂。为了验证这一假设，我们将首先确定NAD如何介导其共佐剂特性（目的1）。在aims 2中，我们将确定细胞外NAD如何调节对流感病毒的免疫反应；在aims 3中，我们将测试含有NAD的疫苗在增强免疫保护以对抗新血清型流感病毒感染方面的功效。这些实验将促进新一类辅助佐剂的开发，这些佐剂可安全地用于人类，以改善细胞介导的对流感等致病性细胞内生物的免疫保护。与公共卫生有关。在美国，流感病毒感染引起了显著的发病率和死亡率。在典型的一年里，美国约有10万人因流感住院，2万至3.5万人死于病毒感染或继发性细菌感染。此外，新出现的流感毒株，例如1997年在香港出现的高毒力H5N1变种，有可能引发全球大流行，造成毁灭性的社会和经济后果。因此，NIAID的最高优先事项之一（NOT-AI-05-013）是我们开发更有效的流感疫苗，以防止各种不同的病毒血清型。

DESCRIPTION (provided by applicant): Influenza virus infections cause significant morbidity and mortality in the US and world. Since the current inactivated virus vaccines do not induce protective immunity to emerging strains of influenza virus, new vaccines are urgently needed. Unfortunately, the current inactivated virus vaccines do not contain adjuvant and do not induce lasting cellular immunity. Since the only adjuvant approved for use in humans is alum and alum enhances type 2 immune responses that are often detrimental for lung function, it is important to identify new, safe adjuvants that can be used in an influenza vaccine. Most commonly used experimental adjuvants are pathogen-derived and enhance immune responses by triggering Toll-like receptors (TLRs) which induce inflammation and tissue damage and activate dendritic cells. However, other molecules, unrelated to TLRs, also have the potential to modulate immune responses. One such molecule is the ecto-enzyme CD38 which catabolizes extracellular NAD, released by damaged and dying cells, to produce Ca2+mobilizing metabolites that modulate chemokine receptor signaling. CD38 and its substrate, NAD, are required for leukocyte migration and are also important for the generation of functional effector T cells. Interestingly, NAD, when co-administered with protein antigens and subthreshold amounts of adjuvant, significantly enhances T cell dependent immune responses. Based on these data, we hypothesize that NAD functions as a "co-adjuvant" to enhance innate and adaptive immune responses and that CD38 and extracellular NAD represent a novel class of immune modulators that are distinct from the TLRs. To test this hypothesis, we will first determine how NAD mediates its co-adjuvant properties (Aim 1). In Aim 2, we will determine how extracellular NAD regulates immune responses to influenza virus and in Aim 3, we will test the efficacy of a NAD-containing vaccine in enhancing immune protection to challenge infection with a new serotype of influenza virus. These experiments will facilitate the development of a new class of co-adjuvants that can be used safely in humans to improve cell-mediated immune protection to pathogenic intracellular organisms like influenza. Relevance to public health. Infections with influenza virus cause significant morbidity and mortality in the United States. In a typical year, approximately 100,000 peoples are hospitalized in the US due to influenza and 20,000-35,000 people die from the viral infection or secondary bacterial infections. Furthermore, the new emerging strains of influenza, such as the highly virulent H5N1 variant that appeared in Hong Kong in 1997, have the potential to trigger a worldwide pandemic with devastating social and economic consequences. Thus, it is one of NIAID's highest priorities (NOT-AI-05-013) that we develop more effective influenza vaccines that are protective against a wide array of different viral serotypes.