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Title: Influenza A virus PB1-F2 protein expression is regulated in a strain-specific manner by sequences located downstream of the PB1-F2 initiation codon

Author
item BUEHLER, JASON - IOWA STATE UNIVERSITY
item NAVI, DEEPAK - IOWA STATE UNIVERSITY
item Baker, Amy
item LAGER, KELLY
item MILLER, CATHY - IOWA STATE UNIVERSITY

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/17/2013
Publication Date: 10/1/2013
Citation: Buehler, J., Navi, D., Lorusso, A., Vincent, A., Lager, K., Miller, C.L. 2013. Influenza A virus PB1-F2 protein expression is regulated in a strain-specific manner by sequences located downstream of the PB1-F2 initiation codon. Journal of Virology. 87(19):10687-10699.

Interpretive Summary: Swine influenza is a pig disease that causes significant economic loss for pork producers. Although vaccines are available to help fight this respiratory disease, they may not work well all of the time because swine influenza virus, the cause of swine influenza, can rapidly mutate. The mutations can thwart the effectiveness of currently available vaccines. This is a challenge since the virus can change faster than new vaccines can be designed, produced, and distributed. One approach to "beating" the virus is to study how it functions in the pig with the anticipation that such research may lead to the development of better vaccines. This paper describes a series of studies investigating the molecular regulation of one of the swine influenza virus proteins, PB1-F2. Results from this work indicate the regulation is a complicated process. In addition, differences in the activity of PB1-F2 were found between swine influenza and human influenza viruses suggesting this protein may function differently among species.

Technical Abstract: Translation of influenza A virus PB1-F2 occurs in a second open reading frame (ORF) of the PB1 gene segment. PB1-F2 has been implicated in regulation of polymerase activity, immunopathology, susceptibility to secondary bacterial infection, and induction of apoptosis. Experimental evidence of PB1-F2 molecular function during infection has been primarily collected from human and avian viral isolates. As the 2009 H1N1 (H1N1pdm09) pandemic highlighted, some swine-derived influenza viruses have the capacity to infect human hosts and emerge as a pandemic. Understanding the impact that pathogenicity factors in swine isolates may have on both human and swine health could aid in early identification of viruses with pandemic potential. Studies examining PB1-F2 from swine isolates have focused primarily on H1N1pdm09, which does not encode PB1-F2, but was engineered to encode a full-length PB1-F2 ORF to assess the impact on viral replication and pathogenicity. However, experimental evidence of H1N1pdm09 PB1-F2 protein expression from swine-lineage viruses has not been demonstrated. Here we reveal that during infection, PB1-F2 expression levels are substantially different between swine and human influenza viruses. We provide evidence that PB1-F2 expression is regulated at the translational level, with very low levels of PB1-F2 expression from swine-lineage viruses relative to a human isolate PB1-F2. Translational regulation of PB1-F2 expression was mapped to two independent regions within the PB1 mRNA, located within and downstream of the PB1-F2 ORF. Our data suggest that encoding a full-length PB1-F2 at the sequence level may not be predictive of PB1-F2 expression in infected cells for all influenza A viruses.