REASSORTMENT AND GENE SELECTION OF INFLUENZA VIRUSES IN THE FERRET MODEL AND POTENTIAL PLATFORMS FOR IN VIVO REVERSE GENETICS

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2014

Authors

Angel, Matthew Gray

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Abstract

Influenza A virus is a highly infectious agent that cause seasonal epidemics affecting 5-15% of the world population with mild to severe illness and possibly death. While this pathogen represents a significant disease burden to the human population, it can also infect a wide range of animals including swine and land-based poultry, which are thought to serve as intermediate hosts between the human and natural wild aquatic bird reservoir. Here, two viruses, a swine-origin pandemic H1N1 and a seasonal human H3N2 are examined for segment fitness during co-infection of in vivo animal models. In three independent co-infections, reassortment between seasonal and pandemic viruses resulted in the selection of an H1N2 virus with a seasonal PB1 with an otherwise pandemic internal gene constellation. Selection for the seasonal PB1 and NA as well as the pandemic M segment was observed to occur rapidly during segment resolution. As pandemic M gene reassortant strains are being consistently identified in the field, studies were performed to identify the genetic determinants in pandemic M gene selection. Research here shows that both the M1 capsid protein and M2 ion channel from the pandemic virus are sufficient to drive the selection of the entire M segment. As swine represent an important intermediate host for the adaptation of potentially pandemic viruses, including pandemic M gene reassortant strains, alternative DNA and recombinant baculovirus-based platforms are investigated for their ability to generate influenza viruses from porcine polymerase I promoters and serve as potential vaccine candidates. Research here shows that influenza A virus can be rescued de novo using the porcine polymerase I promoter in an eight plasmid system. Furthermore, a single bacmid can be constructed that rescues influenza virus or baculovirus encoding the influenza reverse genetic system in mammalian tissue culture or Sf9 cells, respectively. These represent a new generation of species-tailored vaccine platforms.

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