Structure and Function of Viral Immunoevasins

这项工作的重点是了解控制先天免疫系统和获得性免疫系统细胞识别感染病原体(如病毒)的细胞的初始步骤的分子细节。了解免疫系统识别的病毒编码分子相互作用的功能、机制、结构和进化，不仅可以更深入地了解免疫系统中的分子相互作用和细胞-细胞相互作用，而且可能导致合理的干预病毒感染和肿瘤的方法。特别是，我们从生物物理和结构的角度研究了主要组织相容性复合体(MHC)编码的分子大家族的代表性成员。我们感兴趣的是MHC-I分子如何分别通过自然杀伤细胞(NK)和T细胞受体与自然杀伤细胞(NK)和T淋巴细胞上的受体相互作用。疱疹病毒家族的大型DNA病毒产生模仿宿主MHC-I分子的蛋白质，作为其免疫规避策略的一部分，我们致力于了解由小鼠巨细胞病毒(MCMV)编码的一组MHC-I(称为MHC-IV)分子的功能、细胞表达和结构。在过去，我们研究了MHC-IV家族的几个成员的表达和结合，特别是分子m144、m152和m153。最近来自其他实验室的实验已经发现了一种由传染性软疣病毒MC80编码的新的免疫EVASIN，它通过与蛋白质负载复合体中的Tapasin相互作用来阻碍抗原递送，并将Tapasin引导到内质网降解途径。我们已经表达和纯化了一种重组形式的MC80蛋白，用于结构和结合研究，并期望所获得的基础知识将增强我们对MHC多肽加载途径的理解。

The focus of this work has been to understand the molecular details that control initial steps in the recognition of cells infected with pathogens such as viruses by cells of the innate and adaptive immune systems. Understanding the function, mechanism, structure, and evolution of the interaction of virus-encoded molecules recognized by the immune system can lead not only to a deeper understanding of molecular interactions in general and of cell-cell interactions in the immune system, but also may lead to rational approaches to intervention in virus infection and neoplasia. In particular, we study representative members of the large family of major histocompatibility complex (MHC)-encoded molecules from a biophysical and structural perspective. We are interested in how MHC-I molecules interact with receptors on natural killer (NK) cells and on T lymphocytes through their NK and T cell receptors, respectively. Large DNA viruses of the herpesvirus family produce proteins that mimic host MHC-I molecules as part of their immunoevasive strategy, and we have directed our efforts to understand the function, cellular expression, and structure of a set of these MHC-I (referred to as MHC-Iv) molecules encoded by the mouse cytomegalovirus (mCMV). In the past we studied expression and binding of several members of the MHC-Iv family, in particular the molecules, m144, m152, and m153. Recent experiments from other labs have identified a novel immunoevasin encoded by the Molluscum contagiosum virus, MC80, that impedes antigen presentation by interacting with tapasin in the protein loading complex, and directs tapasin to an endoplasmic reticulum degradative pathway. We have expressed and purified a recombinant form of the MC80 protein for structural and binding studies, and expect that the basic knowledge gained will enhance our understanding of the MHC peptide loading pathway.