Foot-and-mouth disease virus entry: RNA release and membrane penetration

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Foot-and-mouth disease virus (FMDV) is one of the most important pathogens affecting agricultural livestock. It is endemic in much of the world, especially in the developing world where its presence restricts the ability to export animal products to disease free countries and so adversely affects rural economies. The virus is one of the most infectious agents known and its ability to cause economic and social havoc was amply demonstrated by the outbreak in the UK in 2001 which cost the country ~£10 billion. FMDV is a member of the picornavirus family which includes other viruses such as poliovirus and rhinovirus (the common cold virus). One of the least well understood steps in the infection process by this family of viruses is how the virus particle is 'uncoated' and transports its genetic material (the blueprint for new virus) across the cell membrane to initiate an infection. We have been studying this process, in collaboration with other laboratories, using poliovirus (PV), which is the best understood of all picornaviruses. From this work, a model of how the infection process is achieved by PV is slowly evolving. It appears to be an elegant and sophisticated mechanism involving a series of intermediate particles. However, FMDV particles are known to have very different properties to those of PV and appear to behave differently during the infection process and this makes it difficult to extrapolate the PV model to FMDV. We intend to apply the novel techniques that we have developed in recent years for studying PV to investigate in detail the mechanism of cell entry by FMDV. These methods use artificial lipid membrane structures to mimic cellular membranes in such a way that they can be finely controlled and examined in the laboratory. We will attempt to mimic the infectious process using these systems and examine the intermediate structures formed during the uncoating of the virus and their effects on the properties of the membranes themselves. In this way we hope to gain insight into how the virus uncoats and projects its RNA genome across an artificial equivalent of a cell membrane. Although these studies are of immediate academic interest, a better understanding of the infection process may also have more practical value in the longer term. For example, alterations in virus structure during the infection process may expose new targets for improved diagnosis of the disease or for the development of vaccines or antiviral drugs to block infection, as has been shown for HIV.