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ISSN 2500-2236
DOI-prefix: 10.18527/2500-2236

Enhancement of the immunogenicity of influenza A virus by the inhibition of immunosuppressive function of NS1 protein


received: 2018-07-03    accepted: 2018-08-01    published: 2018-09-28   

Kirill A. Vasilyev1#, Maria A. Yukhneva1, Anna-Polina S. Shurygina1, Marina A. Stukova1, Andrej Y.Egorov1,2

Author Affiliations

1 Smorodintsev Research Institute of Influenza, St. Petersburg, Russian Federation
2 University of Natural Resources and Life Sciences, Vienna, Austria
# Corresponding author: Kirill Vasilyev: kirill.vasilyev@influenza.spb.ru


Abstract

Truncation of the nonstructural NS1 protein is a novel approach for the generation of immunogenic attenuated influenza viruses, however, the innate immune mechanisms that cause the increased immunogenicity of influenza viruses with altered NS1 protein are poorly understood. The goal of this study was to compare the immune response in mice immunized with two variants of A/Puerto Rico/8/1934 (A/PR8) influenza virus: the wild type virus (А/PR8/full NS) and the variant with a NS1 protein shortened to 124 amino acid residues (А/PR8/NS124). The investigated parameters of immunity included the cytokine production, the dynamic variation of the innate immune cells populations and the rate of influenza-specific T-cellular response. Considering that studied viruses differ in the replication capacity in the respiratory tract, an intraperitoneal route of administration was chosen. The levels of interferon β (IFNβ), tumor necrosis factor α (TNFα), monocyte chemo-attractant protein 1 (MCP1), interleukin 6 (IL6) and IL27 in peritoneal washes of mice immunized with А/PR8/NS124 were significantly higher in comparison to the mice infected with the wild-type virus. The А/PR8/NS124 treated group showed delayed attraction of monocytes and neutrophils and more pronounced reduction of dendritic cells relative content in the peritoneal cavity. The expression level of CD86 activation marker on the major histocompatibility complex II+ (MHC-II+) cells was significantly higher in mice immunized with А/PR8/NS124 than in the group infected with А/PR8/full NS. Finally, immunization with А/PR8/NS124 led to the increased formation of influenza-specific CD8+ effector T-cells characterized by the simultaneous production of IFNγ, IL2, and TNFα. We hypothesize that elevated cytokine production, enhanced dendritic cell migration, and increased CD86 expression on antigen-presenting cells upon immunization with А/PR8/NS124 lead to a more effective presentation of viral antigens and therefore promote an increased antigen-specific CD8+ immune response. 


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