Apoptosis Induction and Inhibition by Modified Vaccinia Virus Ankara during Infection of Human and Mouse Cells

病毒的复制需要宿主细胞的完整性。因此，细胞凋亡是宿主可以对抗病毒感染的有效防御。为了对抗宿主细胞凋亡，许多病毒携带其产物干扰凋亡信号转导的基因。痘病毒修饰的安卡拉牛痘病毒（MVA）特别编码一种蛋白质F1 L，其可以抑制线粒体凋亡途径的操作。在我们的初步工作中，我们已经确定了一些因素，建立了一个平衡，由MVA感染的人类和小鼠细胞的增殖诱导，这是在同一时间由F1 L抵消。最近获得的F1 L的晶体结构和功能测试出乎意料地将其定义为Bcl-2样蛋白。本项目的第一个目标是通过诱变和详细的功能分析来精确定义F1 L的结构-功能。在第二部分中，我们的目的是了解MVA感染过程中F1 L的分子作用，通过重点分析受感染细胞中F1 L阻断的凋亡事件和分子。第三部分的重点将在于上游机制，导致从病毒的识别到启动细胞凋亡的MVA。我们相信，我们目前对MVA感染的理解为我们提供了一个很好的机会，以确定哺乳动物细胞在病毒感染期间建立的增殖诱导和抑制平衡的分子细节。

Viruses require the integrity of the host cell for their replication. Apoptosis is therefore an effective defence the host can muster against viral infection. To counter host cell apoptosis, many viruses carry genes whose products interfere with apoptotic signal transduction. The poxvirus Modified Vaccinia Virus Ankara (MVA) encodes in particular one protein, F1L, which can inhibit operation of the mitochondrial apoptotic pathway. In our preliminary work, we have defined a number of factors that establish a balance consisting of apoptosis-induction by MVA-infection of human and murine cells, which is at the same time countered by F1L. The recently obtained crystal structure and functional testing of F1L define it unexpectedly as a Bcl-2-like protein. The first aim of this project is an exact structure-function definition of F1L action by mutagenesis and detailed functional analysis. In the second part, we aim at understanding the molecular action of F1L during MVA infection by focussing on the analysis of the apoptotic events and molecules that are blocked by F1L in an infected cell. The focus of the third part will lie on the upstream mechanisms that lead from the recognition of the virus up to the initiation of apoptosis by MVA. We believe that our present understanding of MVA-infection affords us with an excellent opportunity to work out molecular details of the balance of apoptosis-induction and -inhibition that is established during viral infection of mammalian cells.