Abstract
PB1-F2 is a multifunctional protein and contributes to the pathogenicity of influenza A viruses. PB1-F2 is known to have strain and cell specific functions. In this study we have investigated the apoptotic and inflammatory responses of PB1-F2 protein from influenza viruses of diverse pathogenicities in A549 lung epithelial cells. Overexpression of PB1-F2 resulted in apoptosis and heightened inflammatory response in A549 cells. Comparison revealed that the response varied with each subtype. PB1-F2 protein from highly pathogenic H5N1 virus induced least apoptosis but maximum inflammatory response. Results indicated that apoptosis was mediated through death receptor ligands TNFα and TRAIL via Caspase 8 activation. Significant induction of cytokines/chemokines CXCL10, CCL5, CCL2, IFNα, and IL-6 was noted in A549 cells transfected with PB1-F2 gene construct of 2008 West Bengal H5N1 virus (H5N1-WB). On the contrary, PB1-F2 construct from 2007 highly pathogenic H5N1 isolate (H5N1-M) with truncated N-terminal region did not evoke as exuberant inflammatory response as the other H5N1-WB with full length PB1-F2, signifying the importance of N-terminal region of PB1-F2. Sequence analysis revealed that PB1-F2 proteins derived from different influenza viruses varied at multiple amino acid positions. The secondary structure prediction showed each of the PB1-F2 proteins had distinct helix-loop-helix structure. Thus, our data substantiate the notion that the contribution of PB1-F2 to influenza pathogenicity is greatly strain specific and involves multiple host factors. This data demonstrates that PB1-F2 protein of influenza A virus, when expressed independently is minimally apoptotic and strongly influences the early host response in A549 cells.
Highlights
Influenza is pathogenic viral disease, causing the emergence of newer epidemics and pandemics in mammals [1, 2]
We used PB1-F2 protein belonging to different subtypes of Influenza A virus (IAV) and investigated its ability to induce apoptosis and modulate inflammatory response in transfected A549 cells
Since evolutionarily IAV moved from avian hosts to mammals [22], the amino acid sequence was compared with PB1-F2 protein of highly pathogenic avian influenza-H5N1 (H5N1-WB) virus
Summary
Influenza is pathogenic viral disease, causing the emergence of newer epidemics and pandemics in mammals [1, 2]. Influenza A virus (IAV) causes acute respiratory inflammation in humans and symptoms include high fever, body aches, and fatigue [4]. PB1-F2 is the second protein encoded by the +1 alternate open reading frame within the PB1 gene. It is translated from the fourth initiation codon via a leaky ribosomal scanning mechanism wherein 43S ribosomal complex bypasses the PB1 start codon and two additional intervening AUG codons [6, 7]. Proteins encoded by PB1 gene have translational interdependence, Advances in Virology which makes it difficult to understand their relative contributions to the replication cycle and pathogenicity of IAV [4, 5]
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