Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses.

Robert Jan Lebbink,Stine H Rahbek,Søren R Paludan,Martin K Thomsen,Chaoyang Sun ,Simon Kok Jensen ,Kasper Severinsen,Anne Louise Hansen,Rune Hartmann,Mogens Duch,Jacob Giehm Mikkelsen ,Christian K Holm,Veit Hornung,Dara Burdette ,Camilla G Nielsen,Anders Laustsen,Yingluo Xiong,Zhaozaho Jiang,Hans Henrik Gad,Shervin Bahrami,Martin R Jakobsen,Rasmus O Bak,Katherine A Fitzgerald

doi:10.1038/ncomms10680

Abstract

Stimulator of interferon genes (STING) is known be involved in control of DNA viruses but has an unexplored role in control of RNA viruses. During infection with DNA viruses STING is activated downstream of cGAMP synthase (cGAS) to induce type I interferon. Here we identify a STING-dependent, cGAS-independent pathway important for full interferon production and antiviral control of enveloped RNA viruses, including influenza A virus (IAV). Further, IAV interacts with STING through its conserved hemagglutinin fusion peptide (FP). Interestingly, FP antagonizes interferon production induced by membrane fusion or IAV but not by cGAMP or DNA. Similar to the enveloped RNA viruses, membrane fusion stimulates interferon production in a STING-dependent but cGAS-independent manner. Abolishment of this pathway led to reduced interferon production and impaired control of enveloped RNA viruses. Thus, enveloped RNA viruses stimulate a cGAS-independent STING pathway, which is targeted by IAV.

Highlights

Cells respond to infections and alterations in cellular homoeostasis by stimulation of repair, death and defence mechanisms[1]
In order to evaluate the role of stimulator of interferon genes (STING) in the stimulation of interferon production by RNA viruses, and to explore the potential involvement of cyclic GMP-AMP (cGAMP) synthase (cGAS), we infected wild-type (WT), STING- and cGAS-deficient murine embryonal fibroblasts (MEFs) with the two paramyxoviruses Newcastle disease virus (NDV) and Sendai virus (SeV) and measured the accumulation of type I interferon in the culture supernatant
DNA viruses are detected by cGAS, which produces 2030 cGAMP to activate STING through direct binding resulting in stimulation of the TANK-binding kinase 1 (TBK1)-IRF3-interferon pathway[24]

Summary

Introduction

Cells respond to infections and alterations in cellular homoeostasis by stimulation of repair, death and defence mechanisms[1]. The innate immune system utilizes pattern-recognition receptors at cell surfaces, in endosomal compartments, and in the cytoplasm to detect immunostimulatory molecules and induce antimicrobial activities[2]. Upon DNA recognition, cGAS produces 2’3’ cGAMP, which binds STING to induce a conformational change. This allows activation of the TANK-binding kinase 1 (TBK1) (refs 6,7), which phosphorylates and activates the transcription factor IRF3 leading to expression of type I interferons (interferon, interferon-a/-b)[5,6,7,8]. STING was first identified as being important in innate immune responses to RNA viruses[9]. The importance of STING in the innate immune defence against RNA viruses was further supported by the identification of RNA viruses that antagonize STING-dependent signalling[10,11,12]. We describe a cGAS-independent STING pathway triggered by enveloped RNA viruses to evoke innate immune responses and demonstrate that this pathway is targeted by influenza A virus (IAV)

Methods

Results

Conclusion