Event Title First Global Alliance for Research on Avian Diseases (GARAD) Conference
Session Title Unknown
Event Date & Time On Wed, 01 Jul 2015 at 11:15:00 - 11:35:00
Venue Edmond J. Safra Lecture Theatre
Abstract Title Influenza A virus PB1-F2: a designer protein with devious functions
Authors Subbiah Elankumaran
Affiliations Department of Biomedical Sciences and Pathobiology, VMCVM, Virginia Tech, Blacksburg, VA, USA
Abstract Content

The influenza A virus (IAV) protein PB1-F2 is considered a virulence factor in primary IAV infection and secondary bacterial pneumonia. Most pandemic and lethal IAV express a full-length PB1-F2 protein and the presence of serine at position 66 (66S) has been identified as a virulence marker. Most swine infleunza viruses (SIV) also possess a full-llength PB1-F2 but truncation or knocking out its expression does not affect pathogeneicity of SIV. The 2009 pandemic swine origin H1N1 influenza virus (pdm09 H1N1) does not express a full-length PB1-F2 and restoring PB1-F2 expression or introduing 66S in pdm09 H1N1 impacted virulence minimally. It is unclear why PB1-F2 of highly pathegenic avian and pandemic mammalian strains is virulence associated. We identified several residues in the C-terminus of PB1-F2 that were unique in pandemic H1N1 1918, H2N2 1957, and H3N2 1968, and highly pathogenic avian IAV strains. There exists a possibility that avian-like PB1-F2 with these unique residues may be acquired by circulating IAV either by mutation or genetic reassortment. We, therefore, hypothesized that specific residues in addition to 66S in the PB1-F2 may modulate virulence of IAV. We found that C-terminal residues 73K, 75R, and 79R together with 66S increased virus replication, decreased type I interferon response and induced fulminant acute respiratory distress syndrome (ARDS) in mice with characteristic clincial and pathological features of acute lung injury (ALI). The lethal phenotypic mutants increased infiltration of neutrophils, inflammatory monocytes with the production of myeloperoxidase in the lungs consistent with ALI. Additional mutations at 74T, and 76V in PB1-F2 protein compensated the effects and alleviated ARDS. Our study suggests that these additional C-terminal residues together with 66S play a role in pathogenicity and may serve as markers for predicting the virulence of IAV.