Antiviral response elicited against avian influenza virus infection following activation of toll-like receptor (TLR)7 signaling pathway is attributable to interleukin (IL)-1β production

Abstract

ObjectiveSingle stranded ribonucleic acid (ssRNA) binds to toll-like receptor (TLR)7 leading to recruitment of immune cells and production of pro-inflammatory cytokines, which has been shown in mammals. In chickens, ssRNA has been shown to elicit antiviral response against infectious bursal disease virus infection. The objectives of this study were to determine the pro-inflammatory mediators that are activated downstream of TLR7 signaling pathway in avian macrophages and their roles in antiviral response against avian influenza virus (AIV) infection.ResultsIn this study, first, we stimulated avian macrophages with the analog of ssRNA, resiquimod, and found that the ssRNA was capable of increasing nitric oxide (NO) and interleukin (IL-1β) production in avian macrophages. Second, we observed when the avian macrophages were stimulated with ssRNA, it elicits an antiviral response against AIV. Finally, we demonstrated that when we blocked the IL-1β response using IL-1 receptor antagonist (IL-1Ra) and the NO production using a selective inhibitor of inducible nitric oxide synthase (iNOS), N-([3-(aminomethyl)phenyl]methyl)ethanimidamide dihydrochloride (1400 W), the antiviral response against AIV is attributable to IL-1β production and not to the NO production. This study provides insights into the mechanisms of antiviral response mediated by ssRNA, particularly against AIV infection.

In Ovo Delivered Toll-Like Receptor 7 Ligand, Resiquimod Enhances Host Responses against Infectious Bronchitis Corona Virus (IBV) Infection

“…Although it has been shown that type 1 IFNs are induced following resiquimod treatment in other animal models [28], our previous work indicated the lack of production of type 1 IFNs and increased production of IL-1β following treatment of avian macrophage with resiquimod [15,27]. In agreement with the observations of these later studies, a lack of production of type IFNs have been shown in avian macrophages following stimulation of these cells with resiquimod [29].…”

“…In addition to CD8α+ T cell recruitment, macrophage recruitment has also been higher in the lungs following pre-hatch delivery of resiquimod. Previously, avian macrophages have been shown to elicit an antiviral response in vitro against avian influenza virus replication [27].…”

“…This autocrine positive feedback loop could possibly explain the increased recruitment of macrophages into the lung tissue along with an associated increase in IL-1β that we observed. IL-1β, originating from avian macrophages, has been shown to elicit antiviral response [27] and it is possible that IL-1β expression in lungs could have played a role in reducing IBV shedding early during the infection.…”

Antiviral responses against chicken respiratory infections: Focus on avian influenza virus and infectious bronchitis virus

“…Additionally, resiquimod, a TLR7 ligand can increase IL-1β production in chicken macrophages, which leads to stimulation of antiviral responses against AIV. The induction of antiviral response against AIV by TLR7 ligands is attributable to IL-1β production and not to the NO production [66]. In addition, after treatment of embryonated chicken eggs with R848, a TLR7 ligand, IL-1β is upregulated in CAM, which may recruit macrophages to the CAM.…”

Host–Virus Interaction: How Host Cells Defend against Influenza A Virus Infection

“…In plasmacytoid dendritic cells (pDCs), after activation of TLR7 during IAV infection, IRF7 or nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were activated via myeloid differentiation factor 88 (MyD88) to induce type I IFNs [132]. In avian macrophages, activation of TLR7 produced pro-inflammatory molecules such as interleukin (IL)-1β [133]. In addition, in mouse models, TLR7 played an important role in activation of NK cells [134].…”