Search

PB1-F2 is a 90 amino acid protein that is expressed from the +1 open reading frame in the PB1 gene of some influenza A viruses. The PB1-F2 protein has been shown to contribute to viral pathogenicity, but the molecular mechanisms for mediating virulence have been unclear. Previous reports demonstrate that PB1-F2 promotes cell death, causes immunopathology and increases pro-inflammatory responses. Our group has identified a single point mutation from asparagine (N) to serine (S) at position 66 in the PB1-F2 protein that dramatically increases the virulence of highly pathogenic avian H5N1 influenza viruses and of the 1918 pandemic strain. In search for the mechanism by which PB1-F2 N66S increases pathogenicity, we have identified and characterized a novel function of PB1-F2, i.e., interferon antagonism, both in vitro and in the mouse model. Here, we discuss a hypothesis for a possible molecular link between the pro-apoptotic and anti-interferon functions of PB1-F2. [ABSTRACT FROM AUTHOR]

The PB1-F2 protein of influenza A virus can contribute to viral pathogenesis of influenza virus strains. Of note, an N66S amino acid mutation in PB1-F2 has been shown to increase the pathogenesis associated with H5N1 Hong Kong/1997 and H1N1 Brevig Mission/1918 influenza viruses. To identify the mechanism of enhanced immunopathology, we evaluated the host response to two isogenic viruses that differ by a single amino acid at position 66 of the PB1-F2 protein. Various components of the adaptive immune response were ruled out as factors contributing to pathogenesis through knockout mouse studies. Transcriptional profiling of lungs from PB1-F2 66S-infected mice revealed an early delay in innate immune responses. In particular, enhanced activation of type I interferon (IFN) pathway genes, including IFN-β, RIG-I, and numerous interferon-inducible genes, was not observed until day 3 postinfection. The N66S mutant virus caused increased cellularity in the lungs, as a result of monocyte and neutrophil infiltration. Furthermore, numerous cytokines and chemokines related to monocyte and neutrophil migration and maturation were upregulated. The cellular infiltration and increased cytokine expression corresponded to increased PB1-F2 66S titer. These data suggest that PB1-F2 N66S may contribute to the delay of innate immune responses, allowing for unchecked viral growth and ultimately severe immunopathology observed in the lungs. [ABSTRACT FROM AUTHOR]