Poxvirus immune modulators and the host Immune system

描述(申请人提供)：痘病毒表达可溶的和膜结合的蛋白质，直接调节宿主的免疫反应。最近，申请人和他的导师在痘病毒及其哺乳动物宿主中发现了一种可溶性IL-18结合蛋白(IL18BP)，这揭示了一种新的免疫调节策略。IL18是一种促炎细胞因子，在小鼠模型中增强免疫反应并保护其免受微生物感染和肿瘤的侵袭。病毒和宿主IL18BPs能高亲和力地与IL-18结合，并抑制IL-18介导的IFNG诱导。需要详细了解涉及IL-18、其受体和IL18BP的相互作用，并具有治疗意义。从六种不同的痘病毒属获得IL18BP使人们能够对IL18的识别和抑制机制进行详细的分子研究。申请人提出了以下具体目标：第一，通过检查不同痘病毒物种的结合，进一步表征IL-18和IL18BP相互作用的结构/功能关系。然后通过鉴定人IL-18中IL18BPs的主要结合部位，并确定该部位是否与IL18R共有，从而确定IL18BP的作用分子机制。最后，研究与IL18BP有显著同源性但不具有IL-18结合活性的两种传染性软体病毒(MCV)蛋白的功能，并确定IL18BP是否结合和抑制与IL-18密切相关的其他细胞因子。

DESCRIPTION (provided by applicant): Poxviruses express soluble and membrane-bound proteins that directly modulate the host immune response. Recently, a new strategy of immune modulation was revealed by the discovery (by the applicant and his mentor) of a soluble IL-18 binding protein (IL18BP) in both poxviruses and in their mammalian hosts. IL18 is a proinflammatory cytokine that enhances immune responses and protects against microbial infection and tumors in murine models. The viral and host IL18BPs can bind to IL-18 with high affinities and inhibit IL-18-mediated IFNg induction. A detailed understanding of interactions involving IL-18, its receptor and IL18BP is needed, and has therapeutic implications. The availability of IL18BPs from six different genera of poxviruses has allowed detailed molecular studies to be performed on the mechanism of IL-18 recognition and inhibition. The applicant proposes the following specific aims: First, to further characterize the structure/function relationship of the IL-18 and IL18BP interaction by examining binding in different poxvirus species. Then to determine the molecular mechanism of IL18BP function by identifying in human IL-18 the main binding site for IL18BPs and determining whether the site is shared by IL18R. Finally, to investigate the functions of two molluscum contagiosum virus (MCV) proteins that share significant homology with IL18BP but that have no IL-18 binding activity, and determine whether IL18BPs bind and inhibit other cytokines that are closely related to IL-18.