The molecular pathogenesis of human Enteroviruses : construction of infectious cDNA clones of Enteroviruses and development of a mouse model to study the pathogenesis of Enterovirus 71

[Truncated] The main purpose of this PhD project is to develop a mouse model to study the pathogenesis of Enterovirus 71 (EV71) infections. Secondary to this aim is to produce infectious cDNA clones of enteroviruses that are associated with recent outbreaks of hand, foot and mouth disease (HFMD) in the Asia pacific region - which includes EV71, Coxsackievirus Al6 (CAV16) and Echovirus 7 (E7) - for the investigation of molecular virulence determinants. At the commencement of this study a non-human primate model was the only available animal model to study the pathogenesis of EV71 and, even though clones of various human enteroviruses had been constructed, none had yet been created for the above mentioned viruses. Since then, an infectious cDNA clone of EV71 prototype strain (EV71-BrCr), a non-circulating EV71 strain isolated in 1969, has been created by Arita et al. (2005) and was exploited to analyse the temperature sensitive phenotype in cynomolgus monkeys. A mouse-adapted EV71 (MP-4643) with increased virulence was reported by Wang et al. (2004) to harbour mutations in the 5 ' - untranslated region (UTR), VP2 of the capsid protein and in 2C protein compared to the progenitor virus. An oral murine EV71 infection of MP-4643 was then reported by Chen et al. (2004) and found to involve the central nervous system and subsequently showed that retrograde axonal transport was a major route of transmission after intramuscular infection (Chen et al. 2007).