The Sp1-Responsive microRNA-15b Negatively Regulates Rhabdovirus-Triggered Innate Immune Responses in Lower Vertebrates by Targeting TBK1.

Renjie Chang,Qing Chu,Lei Zhang,Tianjun Xu,Weiwei Zheng

doi:10.3389/fimmu.2020.625828

Abstract

As is known to all, the production of type I interferon (IFN) plays pivotal roles in host innate antiviral immunity, and its moderate production play a positive role in promoting the activation of host innate antiviral immune response. However, the virus will establish a persistent infection model by interfering with the production of IFN, thereby evading the organism inherent antiviral immune response. Therefore, it is of great necessity to research the underlying regulatory mechanisms of type I IFN appropriate production under viral invasion. In this study, we report that a Sp1–responsive miR-15b plays a negative role in siniperca chuatsi rhabdovirus (SCRV)-triggered antiviral response in teleost fish. We found that SCRV could dramatically upregulate miiuy croaker miR-15b expression. Enhanced miR-15b could negatively regulate SCRV-triggered antiviral genes and inflammatory cytokines production by targeting TANK-binding kinase 1 (TBK1), thereby accelerating viral replication. Importantly, we found that miR-15b feedback regulates antiviral innate immune response through NF-κB and IRF3 signaling pathways. These findings highlight that miR-15b plays a crucial role in regulating virus–host interactions, which outlines a new regulation mechanism of fish’s innate immune responses.

Highlights

Effective detecting of invading viral pathogens by the host innate immune system is essential for the subsequent developing of antiviral innate and adaptive immune responses, which are necessary for clearance of the viruses
To verify the results obtained by RNASeq profiling, miR-15b expression was examined by quantitative real-time PCR at multiple time points after siniperca chuatsi rhabdovirus (SCRV) infection or different kinds of SCRV infection multiplicity of infection (MOI)
Similar to SCRV infection, poly(I:C) stimulation could enhance miR15b expression in macrophages (Figure 1D). These data verified that miR-15b expression could be increased by SCRV infection, which indicated that miR-15b potentially participates in regulating the immune responses triggered by virus infection

Summary

Introduction

Effective detecting of invading viral pathogens by the host innate immune system is essential for the subsequent developing of antiviral innate and adaptive immune responses, which are necessary for clearance of the viruses. Viruses recognition is conducted through different classes of pattern recognition receptors (PRRs), such as Toll-like receptors, retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), and nucleic acid sensor [1, 2] Upon viral infection, these PRRs recruit different key adaptor protein, such as TIR domain-containing adapter-inducing interferon-b (TRIF), miR-15b Modulates Antiviral Immune Response mitochondria antiviral-signaling protein (MAVS), or stimulator of interferon genes (STING), which triggers the activation of TANK-binding kinase 1 (TBK1). The IKKrelated kinases TBK1 and IKKε function as pivotal components of the virus-activated kinase complex that subsequently phosphorylate and activate IRF3 to induce type I IFN production. TBK1 phosphorylates the Spring viremia of carp virus (SVCV) P protein, reduces the processes of IFN regulatory factor 3 (IRF3) phosphorylation, and inhibits the production of IFN, which in turn promotes viral replication. There are growing evidences to indicate that TBK1 activity can be regulated by many molecules in sets of different ways, including phosphorylation, ubiquitination, kinase activity modulation and prevention of functional TBK1-containing complexes formation [15]

Methods

Results

Conclusion