Abstract
Airway inflammation plays a major role in the pathogenesis of influenza viruses and can lead to a fatal outcome. One of the challenging objectives in the field of influenza research is the identification of the molecular bases associated to the immunopathological disorders developed during infection. While its precise function in the virus cycle is still unclear, the viral protein PB1-F2 is proposed to exert a deleterious activity within the infected host. Using an engineered recombinant virus unable to express PB1-F2 and its wild-type homolog, we analyzed and compared the pathogenicity and host response developed by the two viruses in a mouse model. We confirmed that the deletion of PB1-F2 renders the virus less virulent. The global transcriptomic analyses of the infected lungs revealed a potent impact of PB1-F2 on the response developed by the host. Thus, after two days post-infection, PB1-F2 invalidation severely decreased the number of genes activated by the host. PB1-F2 expression induced an increase in the number and level of expression of activated genes linked to cell death, inflammatory response and neutrophil chemotaxis. When generating interactive gene networks specific to PB1-F2, we identified IFN-γ as a central regulator of PB1-F2-regulated genes. The enhanced cell death of airway-recruited leukocytes was evidenced using an apoptosis assay, confirming the pro-apoptotic properties of PB1-F2. Using a NF-kB luciferase adenoviral vector, we were able to quantify in vivo the implication of NF-kB in the inflammation mediated by the influenza virus infection; we found that PB1-F2 expression intensifies the NF-kB activity. Finally, we quantified the neutrophil recruitment within the airways, and showed that this type of leukocyte is more abundant during the infection of the wild-type virus. Collectively, these data demonstrate that PB1-F2 strongly influences the early host response during IAV infection and provides new insights into the mechanisms by which PB1-F2 mediates virulence.
Highlights
Influenza A virus (IAV) commonly causes acute respiratory infection and is one of the most important human pathogens, causing between 250,000 and 500,000 deaths every year around the world [1]
In order to understand the impact of PB1-F2 in the pathogenesis underlying Influenza A virus infection, we engineered a mutant virus unable to express PB1-F2
We identified that PB1-F2 expression enhances the immune cell death and inflammatory responses of mice
Summary
Influenza A virus (IAV) commonly causes acute respiratory infection and is one of the most important human pathogens, causing between 250,000 and 500,000 deaths every year around the world [1]. IAV are enveloped viruses belonging to the Orthomyxoviridae family. Their negative strand RNA genome is composed of 8 segments encoding up to 12 proteins. PB1-F2 is a virulence factor first described 10 years ago [2] This 75–90 amino acid long accessory protein is encoded by an alternative +1 reading frame on segment 2 which encodes the RNA polymerase basic protein 1 (PB1) and N40, an N-terminally truncated version of PB1 lacking transcriptase function [2,3]. PB1-F2 is suspected to contribute to this disproportional response which frequently leads to vital respiratory tissue damage and death of the infected person [5]
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