Center for Investigating Viral Immunity and Antagonism

描述(申请人提供)：在这项中心拨款中，我们建议研究A、B和C类病毒与人类原代细胞的相互作用，从而诱导先天和获得性免疫反应。我们的研究将集中在1)1型干扰素反应的诱导和颠覆的病毒机制和2)树突状细胞的成熟以及这些过程对获得性免疫的影响。这将通过开发新技术来实现，这些技术将全面了解人类对病毒病原体的反应。尽管很明显，大多数病毒(如果不是所有病毒)都编码与免疫逃避有关的基因产物，但人们对这些病毒基因对人类免疫反应的影响知之甚少。我们正计划建立这样的检测方法：1)使用表达病毒拮抗剂的嵌合病毒来识别和表征免疫功能的病毒抑制物；2)在三个阶段产生诱导人类对病毒的免疫反应的分子描述：先天免疫、先天适应界面和适应性免疫。这将通过在基因转录、干扰素信号、细胞因子/细胞表面标记表达和多肽递呈的水平上表征细胞对病毒感染的反应的动力学来完成；以及3)尝试识别影响参与诱导免疫反应的关键基因的转录水平的人类基因多态。开发的技术将被该中心的其他成员用于研究NIAID优先病原体。项目1研究了一种高度致命的人畜共患副粘病毒尼帕病毒，以精确确定四种病毒蛋白(P、V、W和C)抑制天然免疫的作用机制。项目2调查了埃博拉病毒编码的不同蛋白质对树突状细胞功能的调节作用，树突状细胞似乎在自然感染这种出血性负链RNA病毒时受到影响。在项目3中，研究了流感病毒的干扰素拮抗剂蛋白NS1在减弱天然免疫、树突状细胞成熟和刺激T细胞方面的能力。临床核心提供了对技术和研究项目所需的人体样本的可靠访问，此外，它还将生成一个患者临床病史数据库，该数据库将对解释个人免疫反应的差异非常宝贵。行政核心将监督和协调这一应用的研究项目和技术开发组成部分，并组织联席会议，以保证这些组成部分之间更好地协同。我们拟议的中心收集的信息和资源将用于促进人-病原体相互作用的研究，例如对几个A-C类病原体的试点项目的支持。我们提出的研究将在细胞水平上扩大我们对人类对病毒感染的免疫反应的理解，以及对抗1型干扰素反应的病毒基因的作用机制和对获得性免疫和致病性的影响。此外，开发的技术将有助于分析调节先天和获得性免疫反应的人类/病原体相互作用。

DESCRIPTION (provided by applicant): In this center grant we propose to study interactions of Category A, B and C viruses with human primary cells resulting in induction of innate and adaptive immune responses. Our investigations will be focused on viral mechanisms of induction and subversion of 1) type 1 interferon responses and 2) maturation of dendritic cells and the impact that these processes have on adaptive immunity. This will be done through the development of novel technologies that will provide a comprehensive profile of human responses to viral pathogens. Although it has become apparent that most if not all viruses encode gene products implicated in evasion of immunity, very little is known of the impact of these viral genes on the human immune response. We are planning to establish assays that will 1) identify and characterize viral inhibitors of immune function using chimeric viruses expressing such antagonists; 2) generate a molecular depiction of the induction of the human immune response against viruses at three stages: innate immunity, the innate-adaptive interface, and adaptive immunity. This will be done by characterizing the kinetics of the cellular response to viral infection at the levels of gene transcription, IFN signaling, cytokine/cell surface marker expression and peptide presentation; and 3) attempt to identify human gene polymorphisms that impact the levels of transcription of critical genes involved in the induction of the immune response. The technology developed will be utilized by other members of the center to study NIAID priority pathogens. Project 1 investigates the highly lethal Nipah virus, a zoonotic paramyxovirus, to precisely define the mechanisms of action of four viral proteins (P,V,W, and C) shown to inhibit innate immunity. Project 2 investigates the role that different proteins encoded by Ebola virus have on modulation of dendritic cell function, which appears to be affected during natural infections with this hemorrhagic negative strand RNA virus. In Project 3, the IFN antagonist protein NS1 of influenza virus is investigated with respect to its ability to attenuate innate immunity, dendritic cell maturation and stimulation of T cells. Reliable access to human samples required for both the technological and research projects is provided by the clinical core , which in addition will generate a database of patient clinical histories that will be invaluable for interpretation of differences in immune responses among individuals. Administrative core will oversee and coordinate the research projects and technology development components of this application, and organize joint meetings to guarantee a better synergism among these components. The information and resources gathered by our proposed center will be used to facilitate research in human-pathogen interactions, as exemplified by the support of pilot projects on several category A-C pathogens. Our proposed studies will expand our understanding of human immune responses to virus infection at the cellular level and of the mechanism of action and the impact on adaptive immunity and pathogenicity of viral genes that antagonize the type 1 IFN response. In addition, the developed technology will facilitate the analysis of human/pathogen interactions that modulate the innate and adaptive immune response.