Studentship: Evasion of host innate immunity by Newcastle disease virus (NDV) and its pathogenic consequences

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Newcastle disease virus is an important pathogen of both domesticated/wild birds. The disease is a worldwide problem with serious economic impact and sporadic outbreaks occur frequently. In the UK the disease is notifiable. The last outbreak in chickens/turkeys in the UK was 1997 but it occurred in pheasants in Southeast England in 2005 & partridges in Scotland in 2006. The disease was only controlled by expensive surveillance/slaughter policy. NDV is associated with 3 distinct pathogenic phenotypes; lentogenic, mesogenic, velogenic. Understanding molecular determinants behind these differences will be essential for more effective control measures such as vaccine production/population screening. NDV is a paramyxovirus and our experience on other paramyxoviruses demonstrates that virulence is associated with the ability to evade the host innate immune response especially the production of, and signalling response to, type I interferon. Evasion of IFN induction is a property of viral V protein. We’ve shown that paramyxoviral V proteins bind to and inhibit the pattern recognition receptor (PRR) mda5; more recently we’ve shown that V proteins inhibit the activation of the PRR RIG-I by recruiting it into an inhibitory complex, with a host factor called LGP2. The sequences of the V proteins of NDV strains of differing pathogenicity show clear differences in the domain known to interact with mda5 and LGP2. Our preliminary data indicate that these differences affect the affinity of NDV V protein for chicken mda5 and that the V protein from a lentogenic strain is less effective at inhibiting mda5 function than from a pathogenic strain. We aim to characterise these interactions in more detail and explore interactions with newly identified targets of V proteins such as chicken IRF7. We will determine if there is a tight link between control of type I IFN induction and pathogenicity; such a link would be valuable in designing attenuated strains for vaccine candidates.

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