Development of live attenuated vaccine candidates for Newcastle Disease Virus

点击翻译按钮获取中文摘要

The farming of poultry and production of eggs is of growing economic importance to Thailand, as well as other countries in the region, but like all livestock industries, animal production is susceptible to disruption by outbreaks of infectious disease. Newcastle Disease Virus is a major pathogen of birds and causes significant economic losses in first world and developing countries, requiring widespread slaughter policies for control. Although Thailand has remained free from NDV since 2014, neighbouring countries have suffered NDV outbreaks; Thai exports of poultry have correspondingly increased. Keeping flocks free from NDV is thus of paramount importance. Available vaccines are not very effective at protecting birds against genotype VII NDV currently circulating in regions of Asia and elsewhere. In this proposal we aim to use our knowledge of the avian innate immune response to engineer a genotype VII virus to be incapable of evading host innate immunity (specifically the interferon system) and therefore generate a lead candidate for a live attenuated vaccine. Our approach has several interdependent phases: We will initially analyse the properties of the "V" protein of a highly pathogenic ("velogenic") genotype VII NDV as an antagonist of interferon induction or the interferon response and compare this with the "V" protein of an apathogenic ("lentogenic") strain. We will identify key host target proteins that are signalling molecules involved in the interferon system and which interact with the V proteins, and we will validate the importance of these proteins in avian innate immunity using in vitro assays. We will characterise the V/host interactions at the molecular level and will identify V determinants that are essential for interactions. We will then engineer both lentogenic and velogenic (genotype VII) strains of NDV to express altered V proteins that cannot interact with the key host target proteins and by extension which render the virus unable to evade host innate immunity. We will test for attenuation of these viruses by experimental infections in chickens, and we will determine whether this correlates with a failure to block interferon induction or enhanced interferon sensitivity in vivo.