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Microbiology and Immunology

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Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling.

TitleInduction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling.
Publication TypeJournal Article
Year of Publication2019
AuthorsWei F, Jiang Z, Sun H, Pu J, Sun Y, Wang M, Tong Q, Bi Y, Ma X, Gao GFu, Liu J
JournalPLoS Pathog
Volume15
Issue10
Paginatione1008062
Date Published2019 10
ISSN1553-7374
KeywordsAnimals, Antiviral Agents, Cells, Cultured, Down-Regulation, Host-Pathogen Interactions, Immune Evasion, Immunity, Innate, Interferon Type I, Male, Mice, Mice, Knockout, NF-kappa B, Orthomyxoviridae, Orthomyxoviridae Infections, Progranulins, Signal Transduction
Abstract

Type I interferons (IFNs) play a critical role in host defense against influenza virus infection, and the mechanism of influenza virus to evade type I IFNs responses remains to be fully understood. Here, we found that progranulin (PGRN) was significantly increased both in vitro and in vivo during influenza virus infection. Using a PGRN knockdown assay and PGRN-deficient mice model, we demonstrated that influenza virus-inducing PGRN negatively regulated type I IFNs production by inhibiting the activation of NF-κB and IRF3 signaling. Furthermore, we showed that PGRN directly interacted with NF-κB essential modulator (NEMO) via its Grn CDE domains. We also verified that PGRN recruited A20 to deubiquitinate K63-linked polyubiquitin chains on NEMO at K264. In addition, we found that macrophage played a major source of PGRN during influenza virus infection, and PGRN neutralizing antibodies could protect against influenza virus-induced lethality in mice. Our data identify a PGRN-mediated IFN evasion pathway exploited by influenza virus with implication in antiviral applications. These findings also provide insights into the functions and crosstalk of PGRN in innate immunity.

DOI10.1371/journal.ppat.1008062
Alternate JournalPLoS Pathog
PubMed ID31585000
PubMed Central IDPMC6795447

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