Understanding foot-and-mouth disease virus (FMDV) replication

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Background: Domesticated animals in the UK (cattle, sheep, goats and pigs) are at risk from FMDV, a highly contagious virus, endemic in many parts of the world. In addition to catastrophic acute infection, the virus can also cause long-term unapparent 'persistent' infections that are difficult to diagnose in the field and complicate disease control. FMDV can also cause persistent infections of wild ruminants (e.g. wildebeest and buffalo) in Africa, thus providing an important reservoir for infection of domestic livestock. There is an urgent need to develop improved strategies for diagnosis and disease control. In order to achieve this, we need a more comprehensive understanding of the molecular details of the viral lifecycle. Objectives: The proposed research will give novel insight into features of the FMDV genome that allow rapid replication/establishment of persistent infections and determine species specificity. They will be used in future attenuated vaccine design. Novelty: Many aspects of FMDV replication are poorly understood. To our knowledge, no similar work is being undertaken elsewhere. Timeliness: Recently, some innovative studies have suggested the importance of viral co-infection in viral replication. We have established a system to look at the cross talk between FMDV co-infections [Herod et al, 2015 and 2016]. We plan to exploit this system here, see below. Experimental approach: We will use a replicon (with GFP reporter) to study replication in mammalian cells. The absence of structural proteins makes this safe to use. The project will involve:1. Identifying new novel roles of FMDV non-structural proteins and precursors in replication, focusing on the polymerase (3D) and primer of replication (VPg) using mutagenesis and replication inhibitors.2. Dissecting the sites of replication i.e. 'replication factories' e.g. by PALM/STORM and EM.