Infectious Bronchitis Coronavirus Inhibits STAT1 Signaling and Requires Accessory Proteins for Resistance to Type I Interferon Activity

Abstract

The innate immune response is the first line of defense against viruses, and type I interferon (IFN) is a critical component of this response. Similar to other viruses, the gammacoronavirus infectious bronchitis virus (IBV) has evolved under evolutionary pressure to evade and counteract the IFN response to enable its survival. Previously, we reported that IBV induces a delayed activation of the IFN response. In the present work, we describe the resistance of IBV to IFN and the potential role of accessory proteins herein. We show that IBV is fairly resistant to the antiviral state induced by IFN and identify that viral accessory protein 3a is involved in resistance to IFN, as its absence renders IBV less resistant to IFN treatment. In addition to this, we found that independently of its accessory proteins, IBV inhibits IFN-mediated phosphorylation and translocation of STAT1. In summary, we show that IBV uses multiple strategies to counteract the IFN response. IMPORTANCEIn the present study, we show that infectious bronchitis virus (IBV) is resistant to IFN treatment and identify a role for accessory protein 3a in the resistance against the type I IFN response. We also demonstrate that, in a time-dependent manner, IBV effectively interferes with IFN signaling and that its accessory proteins are dispensable for this activity. This study demonstrates that the gammacoronavirus IBV, similar to its mammalian counterparts, has evolved multiple strategies to efficiently counteract the IFN response of its avian host, and it identifies accessory protein 3a as multifaceted antagonist of the avian IFN system. Infectious bronchitis virus (IBV) is a member of the genus Gammacoronavirus, a group of viruses from the order of Nidovirales characterized by a large positive-stranded RNA genome (1). IBV is the causative agent of infectious bronchitis, which is one of the most important viral diseases in chickens, a highly contagious respiratory disease that can spread to the gastrointestinal or the urogenital tract (2, 3). Despite widespread application of inactivated and live attenuated vaccines, infectious bronchitis remains one of the most reported diseases in poultry farms worldwide. Notwithstanding the widespread nature and economic importance of this virus, interactions between IBV and the host immune response remain poorly understood.During the immune response to viruses, the type I interferon (IFN) response plays a pivotal role. Recently, we have shown that IBV induces delayed activation of the interferon response (4) in a manner similar to that of several members of the genus Betacoronavirus, including mouse hepatitis virus (MHV), severe acute respiratory syndrome-associated coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV) (5-8). The observation that coronaviruses delay activation of the IFN response and limit production of IFN suggests that IFN has the ability to hinder their propagation. In apparent contrast, most coronaviruses are relatively resistant to treatment with IFN in vit...

Recombinant live attenuated avian coronavirus vaccines with deletions in the accessory genes 3ab and/or 5ab protect against infectious bronchitis in chickens

“…Apparently the proteins encoded by the accessory genes 3 and 5 do not contribute critically to the replication of IBV in ovo, which is in accordance with previous observations in cell culture cells and in ECEs using recombinant Beaudette virus [9,16,17]. Proteins 3ab and 5ab have recently been associated with the chicken IFN response to IBV infection in cell culture [19][20][21]. However, the ability to induce IFN as well as the sensitivity to the action of IFN is only fully functional during the third and last week of embryonic development [32,33] and develops in ECEs with gestational age [33].…”

“…Several lines of evidence indicate, however, that they might have a role in viral pathogenesis in chickens. In particular, these genes are conserved across all IBV field strains [18] and recent studies indicate that the 3a and 3b proteins induced a delayed activation of the type I interferon (IFN) response in vitro, with protein 3a additionally being involved in resistance of IBV to the cellular antiviral state induced by IFN [19,20]. Accessory protein 5b was found to contribute to host cell shut-off, including amongst others the inhibition of translation of type I IFN [21].…”

Inflammatory Mediators in the Mesenteric Lymph Nodes, Site of a Possible Intermediate Phase in the Immune Response to Feline Coronavirus and the Pathogenesis of Feline Infectious Peritonitis?

“…They have also been linked to other coronavirus infections (e.g. STAT1 knock-out mice show a markedly increased susceptibility to SARS-CoV, while avian infectious bronchitis coronavirus uses STAT1 inhibition of IFN responses) (Frieman et al, 2010;Kint et al, 2015). STAT1 and 2 gene transcription levels correlated with type II and I interferon transcription levels, respectively, in our study, while in virus-positive MLNs of cats without FIP, STAT1 and 2 levels (the latter significantly so), as well as IFN-g levels, lay between the other two groups.…”

Identification of an infectious bronchitis coronavirus strain exhibiting a classical genotype but altered antigenicity, pathogenicity, and innate immunity profile

“…It has been reported that small accessary proteins 3a and 3b of IBV can delay the onset of IFN response by interfering with the PRR sensing without disrupting the signaling pathways35. Previous studies have also demonstrated that 3a and 3b accessory proteins of IBV are not essential for replication but can modulate the IFN-β response at the transcriptional and translational level3637. In addition, 5b accessory protein of IBV has been found to shut off host immune response and limit interferon production38.…”