Transcriptomic analysis of host immune and cell death responses associated with the Influenza A Virus PB1-F2 protein
2011
Le Goffic , Ronan(auteur de correspondance) (INRA , Jouy-En-Josas (France). UR 0892 Unité de recherche Virologie et Immunologie Moléculaires) | Leymarie , Olivier (INRA , Jouy-En-Josas (France). UR 0892 Unité de recherche Virologie et Immunologie Moléculaires) | Chevalier , Christophe (INRA , Jouy-En-Josas (France). UR 0892 Unité de recherche Virologie et Immunologie Moléculaires) | Rebours , Emmanuelle (INRA , Jouy-En-Josas (France). UMR 1313 Génétique Animale et Biologie Intégrative) | Da Costa , Bruno (INRA , Jouy-En-Josas (France). UR 0892 Unité de recherche Virologie et Immunologie Moléculaires) | Vidic , Jasmina (INRA , Jouy-En-Josas (France). UR 0892 Unité de recherche Virologie et Immunologie Moléculaires) | Descamps , Delphyne (Institut PasteurInstitut National de la Santé et de la Recherche Médicale, ParisParis(France). Unité de Défense Innée et InflammationU874) | Sallenave , Jean-Michel (Institut PasteurInstitut National de la Santé et de la Recherche MédicaleUniversité Paris 7-Denis Diderot, ParisParisParis(France). Unité de Défense Innée et InflammationU874) | Rauch , Michel (Université de Rennes 1, Rennes(France). EA 4427 SeRAIC) | Samson , Michel (Université de Rennes 1, Rennes(France). EA 4427 SeRAIC) | Delmas , Bernard (INRA , Jouy-En-Josas (France). UR 0892 Unité de recherche Virologie et Immunologie Moléculaires)
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.
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