title: PB1-F2 attenuates virulence of highly pathogenic avian H5N1 influenza virus in chickens.
abstract: Highly pathogenic avian influenza virus (HPAIV) is a permanent threat due to its capacity to cross species barriers and generate severe infections and high mortality in humans. Recent findings have highlighted the potential role of PB1-F2, a small accessory influenza protein, in the pathogenesis process mediated by HPAIV in mammals. In this study, using a recombinant H5N1 HPAIV (wt) and its PB1-F2-deleted mutant (ΔF2), we studied the effects of PB1-F2 in a chicken model. Unexpectedly, when using low inoculation dose we observed that the wt-infected chickens had a higher survival rate than the ΔF2-infected chickens, a feature that contrasts with what is usually observed in mammals. High inoculation dose had similar mortality rate for both viruses, and comparison of the bio-distribution of the two viruses indicated that the expression of PB1-F2 allows a better spreading of the virus within chicken embryos. Transcriptomic profiles of lungs and blood cells were characterized at two days post-infection in chickens inoculated with the wild type (wt) or the ΔF2 mutant viruses. In lungs, the expression of PB1-F2 during the infection induced pathways related to calcium signaling and repressed a large panel of immunological functions. In blood cells, PB1-F2 was associated with a gene signature specific for mitochondrial dysfunction and down-modulated leucocytes activation. Finally we compared the effect of PB1-F2 in lungs of chickens and mice. We identified that gene signature associated to tissue damages is a PB1-F2 feature shared by the two species; by contrast, the early inhibition of immune response mediated by PB1-F2 observed in chickens is not seen in mice. In summary, our data suggest that PB1-F2 expression deeply affect the immune response in chickens in a way that may attenuate pathogenicity at low infection dose, a feature differing from what was previously observed in mammal species.
authors: Unité de Virologie et Immunologie Moléculaires, Unité de Recherche UR892, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors: Olivier
authors: O
authors: Leymarie
authors: National Centre for Foreign Animal Disease, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada.
authors: Carissa
authors: C
authors: Embury-Hyatt
authors: Unité de Virologie et Immunologie Moléculaires, Unité de Recherche UR892, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors: Christophe
authors: C
authors: Chevalier
authors: Unité de Virologie et Immunologie Moléculaires, Unité de Recherche UR892, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors: Luc
authors: L
authors: Jouneau
authors: Centre de Ressources Biologiques pour la Génomique des Animaux Domestiques et d'Intérêt Economique, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors: Marco
authors: M
authors: Moroldo
authors: Unité de Virologie et Immunologie Moléculaires, Unité de Recherche UR892, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors: Bruno
authors: B
authors: Da Costa
authors: National Centre for Foreign Animal Disease, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada.
authors: Yohannes
authors: Y
authors: Berhane
authors: Unité de Virologie et Immunologie Moléculaires, Unité de Recherche UR892, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors: Bernard
authors: B
authors: Delmas
authors: National Centre for Foreign Animal Disease, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors: Hana M
authors: HM
authors: Weingartl
authors: Unité de Virologie et Immunologie Moléculaires, Unité de Recherche UR892, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors: Ronan
authors: R
authors: Le Goffic
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D002642:Chick Embryo; D002645:Chickens; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity*; D005585:Influenza in Birds / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000821:virology*; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D009154:Mutation; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology; D014774:Virulence / Q000235:genetics; D014779:Virus Replication; D017201:Virus Shedding
chemical_list: D000956:Antigens, Viral; C442816:PB1-F2 protein, Influenza A virus; D014764:Viral Proteins