H5N1 influenza virulence; interference in RIG-I detection in different hosts

Bird flu has recently begun circulating in North America in wild birds, infecting poultry and some mammals. Occasionally it can infect humans, and is extremely deadly and has killed half of the 875 people that have been infected in the last 10 years in Asia. Currently circulating strains of this virus have undergone reassortment with N. American influenza strains and have become more virulent in mammals, heightening the possibility of emergence of a new pandemic strain. The sequence variants responsible for increased virulence in mammals are unknown. We are interested in learning what gene sequences of these bird flu viruses make them so lethal in humans and mammals. These viruses also upset the natural ecology of host-pathogen interactions in the reservoir host, since they can also kill ducks, which is not typical of most strains that circulate in wild birds. We know some proteins of the virus are able to shut down innate immunity in mouse and man. In previous work we have shown that some bird flu strains can inhibit human proteins but not avian host proteins, shutting down innate immunity in humans but not ducks (the reservoir host). We will continue our exploration of the viral sequences that make bird flu virulent in avian and human hosts. This will help inform surveillance, since strains that kill ducks may or may not kill humans. We will also continue our study of the networks of proteins involved in fine tuning innate signalling. Finally, since chickens lack the flu detector, we will determine the required proteins and genes needed to reconstitute antiviral function in these cells. Ultimately, we will put the duck innate sensor in chicken cells and experimental chickens to allow direct comparison of the contribution of this pathway to flu defense.