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Title:   Author  item
                                            PENA, LINDOMAR - University Of Marylanditem
                                            Baker, Amyitem
                                            Loving, Crystalitem
                                            Henningson, Jamieitem
                                            Lager, Kellyitem
                                            PEREZ, DANIEL - University Of Maryland
  Submitted to: Journal of General Virology
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 7/17/2012
                                    Publication  Date: 10/1/2012
                                    Citation: Pena, L., Vincent, A.L., Loving, C.L., Henningson, J.N., Lager, K.M., Perez, D.R. 2012. Strain-dependent effects of PB1-F2 of triple reassortant H3N2 influenza viruses in swine. Journal of General Virology. 93(10):2204-2214.Interpretive Summary: The PB1-F2 protein of the influenza A viruses (IAV) acts as a virulence factor in the mouse model of infection. Its contribution to the virulence of IAV in swine, however, remains largely unexplored. PB1-F2 is a small protein present in some influenza viruses but absent in the 2009 pH1N1 and many other swine strains of IAV.  PB1-F2 destroys immune cells and increases lung pathology in mice, but little is known about its effect in natural hosts such as the pig. In this study, we chose two genetically related swine-lineage H3N2 triple reassortant IAVs with the genetic code to produce the PB1-F2 protein to assess the impact of PB1-F2 in viral replication and virulence in pigs. Using molecular techniques and reverse genetics, we disrupted the PB1-F2 open reading frame (ORF) of A/swine/WI/14094/1999 (H3N2) [Sw/99] and A/turkey/OH/313053/2004 (H3N2) [Ty/04]. In pigs, PB1-F2 did not affect viral shedding or viral load in the lungs for any of the strains tested. Interestingly, the Ty/04 PB1-F2 knock-out-infected pigs showed significantly increased lung pathology at 3 days post-infection (dpi) compared to pigs infected with the wt Ty/04 strain. In addition, the lung levels of certain immune mediators, IL-6, IL-8, and IFN-gamma, were differentially regulated by the expression of PB1-F2. Taken together, these results indicate that PB1-F2 modulates viral replication, virulence, and innate immune responses in pigs in a strain-dependent fashion but does not appear to have the dramatic effects seen in the mouse model.
                                Technical Abstract: The PB1-F2 protein of the influenza A viruses (IAV) acts as a virulence factor in the mouse model of infection. Its contribution to the virulence of IAV in swine, however, remains largely unexplored. In this study, we chose two genetically related H3N2 triple reassortant (TR) IAVs to assess the impact of PB1-F2 in viral replication and virulence in pigs. Using reverse genetics, we disrupted the PB1-F2 open reading frame (ORF) of A/swine/WI/14094/1999 (H3N2) [Sw/99] and A/turkey/OH/313053/2004 (H3N2) [Ty/04]. The Ty/04 PB1-F2 knock-out strain showed decreased virus replication in swine respiratory explants, whereas no such effect was observed in the Sw/99 PB1-F2 knock-out, compared to the WT counterparts. In pigs, PB1- F2 did not affect viral shedding or viral load in the lungs for any of these strains. Upon necropsy, PB1-F2 had no effect on the lung pathology caused by Sw/99. Likewise, introduction of the N66S mutation in the Sw/99 background had negligible effects in pigs. Interestingly, the Ty/04 PB1-F2 knock-out-infected pigs showed significantly increased lung pathology at 3 days post infection (dpi) compared to pigs infected with the wt Ty/04 strain. In addition, the pulmonary levels of IL-6, IL-8, and IFN-gamma were differentially regulated by the expression of PB1-F2. Taken together, these results indicate that PB1-F2 modulates viral replication, virulence, and innate immune responses in pigs in a strain-dependent fashion.


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