Transcriptomic Analysis of Host Immune and Cell Death Responses Associated with the Influenza A Virus PB1-F2 Protein

PLoS Pathogens

Emmanuelle Rebours¹  Michel Samson²  Jean-Michel Sallenave²  Delphyne Descamps³  Michel Rauch³  Ronan Le Goffic⁴  Bruno Da Costa⁴  Christophe Chevalier⁴  Jasmina Vidic⁴  Olivier Leymarie⁴  Bernard Delmas⁵ 

[1] Plateforme d'instrumentation et de Compétences en Transcriptomique, Jouy-en-Josas, France;Unité U874 INSERM, Paris, France;Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France;Unité de Virologie et Immunologie Moléculaires, UR 892 INRA, Jouy-en-Josas, France;Université Paris 7-Denis Diderot, Paris, France

关键词: Influenza A virus;    Respiratory infections;    Apoptosis;    Inflammation;    Transcription factors;    Neutrophils;    Gene expression;    Immune response;   

DOI  :  10.1371/journal.ppat.1002202

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY