Poxvirus Modulation of Immune Responses

描述（由申请人提供）：天花作为生物恐怖主义制剂的潜在用途使我们有必要充分了解这种病毒和相关痘病毒科成员的发病机制。痘病毒已经进化出多种机制来调节和逃避宿主免疫反应，损害病毒的识别和清除，并削弱持久的保护性免疫。利用牛痘病毒（VV）作为痘病毒感染的模型，本项目的目标是了解痘病毒如何改变抗原呈递细胞（APCs）的功能。主要的假设是，痘病毒对抗原提呈细胞功能的调节阻止了有效的适应性免疫反应的发展，并增强了病毒的发病机制。为了实现我们的目标，这个应用程序结合了来自一组高度互动的研究人员的四个项目和互补的方法。这些项目将评估疱疹病毒磷酸酶VH1如何改变抗原呈递细胞的信号通路，研究VV如何抑制DC成熟，从而阻止先天和适应性免疫反应的整合，并研究VV改变的生化和细胞特性，以逃避CD1和MHC I类和II类分子的呈递。这四个研究项目将得到行政和资源核心的支持，以帮助研究人员进一步确定痘病毒感染的发病机制，这将导致改进疫苗开发和疾病治疗的战略。

DESCRIPTION (provided by applicant): The potential use of smallpox as a bioterrorism agent has created a need to fully understand the pathogenesis of this virus and related Poxviridae family members. Poxviruses have evolved multiple mechanisms to modulate and evade the host immune response, compromising viral recognition and clearance as well as diminishing long-lasting protective immunity. Using vaccinia virus (VV) as a model of poxvirus infection, the goal of this Program Project is to understand how poxviruses alter the function of antigen presenting cells (APCs). The main hypothesis is that poxvirus modulation of antigen presenting cell function prevents the development of an effective adaptive immune response and enhances viral pathogenesis. To achieve our goal, this application combines four projects from a group of highly interactive investigators with complementary approaches. These projects will assess how the poxvirus phosphatase VH1 alters signaling pathways in antigen presenting cells, investigate how VV inhibits DC maturation which prevents the integration of the innate and adaptive immune responses, and study the biochemical and cellular properties that are altered by VV to escape from the presentation by CD1, and MHC class I and class II molecules. These four research projects will be supported by an administrative and resource core to help the investigators further define the pathogenesis of poxvirus infection, which will lead to improved strategies for vaccine development and disease treatment.