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

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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.