Abstract
PB1-F2 is an accessory protein of most human, avian, swine, equine, and canine influenza A viruses (IAVs). Although it is dispensable for virus replication and growth, it plays significant roles in pathogenesis by interfering with the host innate immune response, inducing death in immune and epithelial cells, altering inflammatory responses, and promoting secondary bacterial pneumonia. The effects of PB1-F2 differ between virus strains and host species. This can at least partially be explained by the presence of multiple PB1-F2 sequence variants, including premature stop codons that lead to the expression of truncated PB1-F2 proteins of different lengths and specific virulence-associated residues that enhance susceptibility to bacterial superinfection. Although there has been a tendency for human seasonal IAV to gradually reduce the number of virulence-associated residues, zoonotic IAVs contain a reservoir of PB1-F2 proteins with full length, virulence-associated sequences. Here, we review the molecular mechanisms by which PB1-F2 may affect influenza virulence, and factors associated with the evolution and selection of this protein.
Highlights
Influenza A viruses (IAVs) cause major human health and economic burdens through both seasonal epidemics and occasional pandemics
Among the mechanisms to be involved in the mitochondrial membrane permeabilization by the PB1-F2 are formation of pores due to accumulation of amyloid fibers [13,17,18], PB1-F2 binding to the voltage-dependent anion channel 1 (VDAC1) and adenine nucleotide translocator 3 (ANT3) proteins in the outer and inner mitochondrial membranes [53], and activation of Drp-1- [33] and Bak/Bax- [11] pathways
Since increased cytokine responses have been linked with severe disease outcomes following influenza infection in humans [66,67], the potential link between PB1-F2 and virulence in humans is supported by animal experiments
Summary
Influenza A viruses (IAVs) cause major human health and economic burdens through both seasonal epidemics and occasional pandemics. SSttrruuccttuurraall cchhaarraacctteerriizzaattiioonn ooff tthhee PPRR88 PPBB11--FF22 rreevveeaalleedd tthhaatt,, ddeeppeennddiinngg oonn ssoollvveenntt ccoonnddiittiioonnss,, iittisisccaappaabbleleoof ffoformrmininggaararnadnodmomcociol iolroar saesceocnodnadryarαy-hαe-hliecalilcaolr oorligoolimgoemricerβicsβh-esheteeetnernicrhicehdesdtrsutrcutuctruer[e1[21,12,31]3. The level of PB1-F2 expression was shown to vary among different IAV strains [22], host and cell types, and be regulated at the translational level by sequences within the PB1 gene segment [23]. Variations within these sequences can result in low levels of protein expression in spite of an apparently intact PB1-F2 ORF [23]
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