The family Picornaviridae includes the enteroviruses, a genus that contains important human pathogenic viruses such as poliovirus and rhinovirus, the causative agents of paralytic poliomyelitis and the “common cold”. These viruses have small, compact genomes, non-enveloped particles and have been extensively studied using reverse genetic analysis for over three decades.
Our current research focusses on the mechanistic analysis of recombination, a significant evolutionary process for these and many other positive-strand RNA viruses. Recombination is the generation of hybrid virus genomes following co-infection of a cell with two closely related viruses. Numerous studies, including collaborative studies with the Simmonds group (Edinburgh) on the epidemiology of enterovirus recombinants, have demonstrated how important this process is in the evolution of this group of viruses.
We are using poliovirus and other enteroviruses as a tractable model system to dissect the viral and cellular determinants that influence the process of recombination. These studies use a combination of reverse genetic and systems-based (e.g. next generation sequencing of virus populations) analysis to understand this process better.
We have recently demonstrated that the process of recombination can be separated into strand exchange and resolution events and further shown that mutations in the viral polymerase can suppress recombination. Our current research involves developing a biochemically-defined in vitro model for recombination, the analysis of the RNA sequences and structures that may enhance recombination and investigating the involvement of cellular proteins in the mechanism.
Why is this important?
Recombination is a major driver of genetic variation in RNA viruses. This genetic variation contributes to the rapid evolution of these viruses to switch host species and is of fundamental importance in viral pathogenesis. Understanding the mechanism of recombination better will help us control cross-species transfer of viruses (or at least know what to expect). More directly, live attenuated viruses that recombine with related naturally co-circulating viruses have been associated with disease outbreaks. If we understand how the viral polymerase contributes to recombination we will be able to generate live attenuated vaccines that cannot recombine. These will be safer vaccines to prevent serious disease in humans and other animals.
Relevant recent publications
Lowry, K , Woodman, A , Cook, J & Evans, DJ 2014, ‘ Recombination in enteroviruses is a biphasic replicative process involving the generation of greater-than genome length ‘imprecise’ intermediates ‘ PLoS Pathogens , vol 10, no. 6, e1004191.
McWilliam Leitch, E. C., Cabrerizo, M., Cardosa, J., Harvala, H., Ivanova, O. E., Koike, S., Kroes, A. C., Lukashev, A., Perera, D., Roivainen, M., Susi, P., Trallero, G., Evans, D. J. & Simmonds, P. 2012. The association of recombination events in the founding and emergence of subgenogroup evolutionary lineages of human enterovirus 71. J Virol 86, 2676-2685.
McWilliam Leitch, E. C., Cabrerizo, M., Cardosa, J., Harvala, H., Ivanova, O. E., Kroes, A. C. M., Lukashev, A., Muir, P., Odoom, J., Roivainen, M., Susi, P., Trallero, G., Evans, D. J. & Simmonds, P. 2010 Evolutionary dynamics and temporal/geographical correlates of recombination in the human enterovirus echovirus types 9, 11, and 30. J Virol 84, 9292-9300.