Influenza A virus PB1‐F2 protein: An ambivalent innate immune modulator and virulence factor

Influenza A virus (IAV) causes not only seasonal respiratory illness, but also outbreaks of more severe disease and pandemics when novel strains emerge as a result of reassortment or interspecies transmission. PB1‐F2 is an IAV protein expressed from the second open reading frame of PB1 gene. Small as it is, PB1‐F2 is a critical virulence factor. Multiple key amino acid residues and motifs of PB1‐F2 have been shown to influence the virulence of IAV in a strain‐ and host‐specific manner, plausibly through the induction of apoptotic cell death, modulation of type I IFN response, activation of inflammasome, and facilitation of secondary bacterial infection. However, the exact role of PB1‐F2 in IAV pathogenesis remains unexplained. Through reanalysis of the current literature, we redefine PB1‐F2 as an ambivalent innate immune modulator that determines IAV infection outcome through induction of immune cell death, differential modulation of early‐ and late‐type I IFN response, and promotion of pathogenic inflammation. PB1‐F2 functions both intracellularly and extracellularly. Further investigations of the mechanistic details of PB1‐F2 action will shed new light on immunopathogenesis of IAV infection. Review on Influenza A virus PB1‐F2 protein and its role in cell death, modulating interferon response and aggravating inflammation.