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

Fanhua Wei,Mingyang Wang,Juan Pu,Yuhai Bi,George Fu Gao,Xiaojing Ma,Yipeng Sun,Honglei Sun,Zhimin Jiang,Qi Tong,Jinhua Liu,Mark T Heise

doi:10.1371/journal.ppat.1008062

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.

Highlights

Influenza virus is one of the most important causes of respiratory tract infection, resulting in approximately 290,000–650,000 deaths each year worldwide
We found that H5N1, PR8 or H9N2 viruses significantly induced PGRN mRNA expression in the lung tissue homogenates of mice at 3 dpi (Fig 1C) (p < 0.01)
Our results showed that PGRN was significantly increased in H7N9 virus-infected patients compared to healthy controls (p = 0.0006) (S1C Fig)

Summary

Introduction

Influenza virus is one of the most important causes of respiratory tract infection, resulting in approximately 290,000–650,000 deaths each year worldwide (http://www.who.int/news-room/ fact-sheets/detail/influenza). Influenza pandemics occur when a novel virus emerges against which a majority of the population has little or no immunity. Avian influenza viruses pose a growing threat to human health, especially the H5, H7 and H9 subtypes prevalent in poultry. Avian H9N2 viruses have caused comparatively few deaths, H9N2 have been shown to exchange genetic materials with emerging zoonotic influenza viruses such as H7N9 and H10N8 subtypes[3, 4]. A promising strategy is to identify novel host factors crucial for viral infection, to understand their interplay with influenza viruses, and subsequently to manipulate them to strengthen host defense against the virus

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