The PB1-F2 virulence protein regulates host ILC2 responses during influenza

Abstract

Abstract Influenza remains a major public health concern. The H1N1 PR8 and CA04 influenza viruses are both pandemic strains, yet they have distinct origins and pathogenicity. In PR8, the PB1-F2 viral protein promotes apoptosis of immune cells and negatively influences viral clearance. In the less virulent CA04 strain, however, the PB1-F2 protein is truncated and nonfunctional. Our aim was to examine the role of PB1-F2 in regulating group II innate lymphoid cell (ILC2) function and host susceptibility to viral infection. We found that in the absence of IFN-γ, ILC2s stimulated by CA04 challenge expressed a robust IL-5 response whereas following PR8 challenge, ILC2s predominantly produced IL-13. We observed increased resistance to CA04 challenge in IFN-g−/− mice, which was dependent on ILC2 production of IL-5 and improved tissue integrity. Conversely, during PR8 infection, ILC2s produced only limited amounts of IL-5, with no effect on tissue integrity. We next investigated infection with PB1-F2 recombinant CA04 and PR8 viruses that were created by gene reassortment. CA04 expressing recombinant PR8 PB1-F2 and PR8 expressing recombinant CA04 PB1-F2 induced an ILC2 phenotype and tissue pathogenicity that were similar to the PB1-F2 donor strains, indicating a detrimental role of full-length PB1-F2 protein on ILC2 function and host resistance. Our results suggest that activation of ILC2s can improve host survival following CA04 infection and that the PR8 PB1-F2 inhibits this ILC2-mediated protection. Our findings suggest the concept of a strain-specific contribution of PB1-F2 and ILC2s in protection against influenza virus infection. (supported by NIH Grant R01 HL140496).