title: The NS1 protein of a human influenza virus inhibits type I interferon production and the induction of antiviral responses in primary human dendritic and respiratory epithelial cells.
abstract: The NS1 protein of the influenza A virus is a potent virulence factor that inhibits type I interferon (IFN) synthesis, allowing the virus to overcome host defenses and replicate efficiently. However, limited studies have been conducted on NS1 function using human virus strains and primary human cells. We used NS1 truncated mutant influenza viruses derived from the human isolate influenza A/TX/91 (TX WT, where WT is wild type) to study the functions of NS1 in infected primary cells. Infection of primary differentiated human tracheo-bronchial epithelial cells with an NS1 truncated mutant demonstrated limited viral replication and enhanced type I IFN induction. Additionally, human dendritic cells (DCs) infected with human NS1 mutant viruses showed higher levels of activation and stimulated naïve T-cells better than TX WT virus-infected DCs. We also compared infections of DCs with TX WT and our previously characterized laboratory strain A/PR/8/34 (PR8) and its NS1 knockout strain, deltaNS1. TX WT-infected DCs displayed higher viral replication than PR8 but had decreased antiviral gene expression at late time points and reduced naïve T-cell stimulation compared to PR8 infections, suggesting an augmented inhibition of IFN production and human DC activation. Our findings show that human-derived influenza A viruses have a high capacity to inhibit the antiviral state in a human system, and here we have evaluated the possible mechanism of this inhibition. Lastly, C-terminal truncations in the NS1 protein of human influenza virus are sufficient to make the virus attenuated and more immunogenic, supporting its use as a live attenuated influenza vaccine in humans.
authors.affiliation: Department of Microbiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Kester
authors.initials: K
authors.lastname: Haye
authors.forename: Svetlana
authors.initials: S
authors.lastname: Burmakina
authors.forename: Thomas
authors.initials: T
authors.lastname: Moran
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandez-Sesma
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002522:Chlorocebus aethiops; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D004847:Epithelial Cells / Q000276:immunology* / Q000821:virology; D005786:Gene Expression Regulation; D006801:Humans; D009980:Influenza A virus / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology; D007251:Influenza, Human / Q000276:immunology* / Q000821:virology; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D017384:Sequence Deletion; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000276:immunology* / Q000378:metabolism; D014779:Virus Replication
chemical_list: C085820:INS1 protein, influenza virus; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D017361:Viral Nonstructural Proteins