Study of the host specificity of PB1-F2-associated virulence

Influenza A viruses cause important diseases in both human and animal. The PB1-F2 protein is a virulence factor expressed by some influenza viruses. Its deleterious action for the infected host is mostly described in mammals, while the available information is scarce in avian hosts. In this work, we compared the effects of PB1-F2 in avian and mammalian hosts by taking advantage of the zoonotic capabilities of an avian H7N1 virus. In vitro, the H7N1 virus did not behave differently when PB1-F2 was deficient while a H3N2 virus devoid of PB1-F2 was clearly less inflammatory. Likewise, when performing in vivo challenges of either chickens or embryonated eggs, with the wild-type or the PB1-F2 deficient virus, no difference could be observed in terms of mortality, host response or tropism. PB1-F2 therefore does not appear to play a major role as a virulence factor in the avian host. However, when infecting NF-κB-luciferase reporter mice with the H7N1 viruses, a massive PB1-F2-dependent inflammation was quantified, highlighting the host specificity of PB1-F2 virulence. Surprisingly, a chimeric 7:1 H3N2 virus harboring an H7N1-origin segment 2 (i.e. expressing the avian PB1-F2) induced a milder inflammatory response than its PB1-F2-deficient counterpart. This result shows that the pro-inflammatory activity of PB1-F2 is governed by complex mechanisms involving components from both the virus and its infected host. Thus, a mere exchange of segment 2 between strains is not sufficient to transmit the deleterious character of PB1-F2.