The Influenza Virus Protein PB1-F2 Increases Viral Pathogenesis through Neutrophil Recruitment and NK Cells Inhibition

• Published in: PloS one 2016-10, Vol.11 (10), p.e0165361-e0165361
• Main Authors: Vidy, Aurore, Maisonnasse, Pauline, Da Costa, Bruno, Delmas, Bernard, Chevalier, Christophe, Le Goffic, Ronan
• Format: Article
• Language: English
• Subjects: Alveoli; Animals; Bacterial infections; Biology and life sciences; Comparative analysis; Cytokines; Cytometry; Development and progression; Epidemics; Female; Flow cytometry; Health aspects; Infections; Inflammation; Inflammation - pathology; Influenza; Influenza A; Influenza A virus; Influenza viruses; Killer cells; Killer Cells, Natural - immunology; Leukocytes (neutrophilic); Life Sciences; Luciferases - metabolism; Lung - immunology; Lung - pathology; Lung - virology; Lungs; Medical research; Medicine and health sciences; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Neutropenia; Neutropenia - complications; Neutropenia - pathology; Neutrophil Infiltration; Neutrophils; Neutrophils - pathology; NF-kappa B - metabolism; Orthomyxoviridae; Orthomyxoviridae Infections - complications; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - mortality; Orthomyxoviridae Infections - virology; Pathogenesis; Pathology; Pneumonia; Proteins; Research and Analysis Methods; RNA polymerase; T-Lymphocytes - pathology; Transcriptome - genetics; Viral Proteins - metabolism; Virulence; Virulence (Microbiology); Virulence factors; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0165361

The influenza A virus (IAV) PB1-F2 protein is a virulence factor contributing to the pathogenesis observed during IAV infections in mammals. In this study, using a mouse model, we compared the host response associated with PB1-F2 with an early transcriptomic signature that was previously associated with neutrophils and consecutively fatal IAV infections. This allowed us to show that PB1-F2 is partly involved in neutrophil-related mechanisms leading to death. Using neutropenic mice, we confirmed that the harmful effect of PB1-F2 is due to an excessive inflammation mediated by an increased neutrophil mobilization. We identified the downstream effects of this PB1-F2-exacerbated neutrophil recruitment. PB1-F2 had no impact on the lymphocyte recruitment in the airways at day 8 pi. However, functional genomics analysis and flow cytometry in broncho-alveolar lavages at 4 days pi revealed that PB1-F2 induced a NK cells deficiency. Thus, our results identify PB1-F2 as an important immune disruptive factor during the IAV infection.