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导致严重的发病率和死亡率。由于目前的灭活病毒疫苗不能诱导对新出现的流感病毒株的保护性免疫，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，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，明矾可增强通常对肺功能有害的2型免疫反应，因此识别可用于流感疫苗的新的、安全的佐剂是重要的。最常用的实验佐剂是病原体衍生的，通过触发Toll样受体(TLRs)来增强免疫反应，TLRs诱导炎症和组织损伤，并激活树突状细胞。然而，其他与TLRs无关的分子也有可能调节免疫反应。一个这样的分子是胞外酶CD38，它分解细胞外NAD，由受损和濒死的细胞释放，产生钙离子动员的代谢物，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，对功能效应性T细胞的产生也很重要。有趣的是，当NAD与蛋白质抗原和亚阈值剂量的佐剂联合使用时，显著增强了T细胞依赖的免疫反应。基于这些数据，我们假设NAD作为增强固有和获得性免疫反应的“辅助佐剂”发挥作用，CD38和细胞外NAD代表一类不同于TLRs的新型免疫调节剂。为了验证这一假设，我们将首先确定NAD如何调节其辅助佐剂特性(目标1)。在目标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，在目标3中，我们将测试含有NAD的疫苗在增强免疫保护方面的效果，以应对新型流感病毒的感染。这些实验将促进一类新的辅助剂的开发，这种辅助剂可以安全地用于人类，以提高对流感等致病细胞内生物的细胞介导的免疫保护。与公共卫生的相关性。在美国，感染流感病毒会导致严重的发病率和死亡率。在美国，每年大约有10万人因流感住院，20,000-35,000人死于病毒感染或继发性细菌感染。此外，新出现的流感新品种，例如1997年在香港出现的高毒力H5N1变种，有可能引发一场全球大流行，造成毁灭性的社会和经济后果。因此，我们开发更有效的流感疫苗，对多种不同的病毒血清型具有保护作用，是NIAID的最优先事项之一(不是-AI-05-013)。

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.