Suppression of Interferon Response and Antiviral Strategies of Bunyaviruses

Abstract

The order Bunyavirales belongs to the class of Ellioviricetes and is classified into fourteen families. Some species of the order Bunyavirales pose potential threats to human health. The continuously increasing research reveals that various viruses within this order achieve immune evasion in the host through suppressing interferon (IFN) response. As the types and nodes of the interferon response pathway are continually updated or enriched, the IFN suppression mechanisms and target points of different virus species within this order are also constantly enriched and exhibit variations. For instance, Puumala virus (PUUV) and Tula virus (TULV) can inhibit IFN response through their functional NSs inhibiting downstream factor IRF3 activity. Nevertheless, the IFN suppression mechanisms of Dabie bandavirus (DBV) and Guertu virus (GTV) are mostly mediated by viral inclusion bodies (IBs) or filamentous structures (FSs). Currently, there are no effective drugs against several viruses belonging to this order that pose significant threats to society and human health. While the discovery, development, and application of antiviral drugs constitute a lengthy process, our focus on key targets in the IFN response suppression process of the virus leads to potential antiviral strategies, which provide references for both basic research and practical applications.

Keywords: NSs; STAT; TBK1; bunyavirus; interferon; targeted therapy.

Figure 1

Anti-viral IFN response pathways and known suppression mechanisms of it in the order Bunyavirales.

Figure 2

Model for DBV and GTV suppressing the IFN antiviral system by NS sequestration of key signaling molecules into IBs or FSs. After Dabie bandavirus (DBV) invades the host cells, TRIM25, tank-binding kinase 1 (TBK1), Ikkε, IFN regulatory factor 7 (IRF7), and STAT2, which are involved in the IFN signaling pathway, interact with DBV NSs and are captured into inclusion bodies (IBs), thereby inhibiting the IFN signaling pathway. TRIM25 is isolated to the viral IBs to inhibit TRIM25-mediated retinoic acid-inducible gene (RIG-I)-Ly-63-linked ubiquitination or activation. Reduction in intracellular free TBK1 and IKKε interferes with TBK1/IKKε- IFN regulatory factor 3 (IRF3)/IRF7 signaling. DBV NSs prevent the nuclear translocation of IRF7 by sequestering it to IBs. The phosphorylation and nuclear translocation of STAT2 are inhibited by IBs, which block type I IFN-stimulated JAK-STAT signaling. STAT1 may be tethered to the viral IBs that block its nuclear translocation, resulting in the inhibition of IFN signaling and IFN-stimulated genes (ISGs) expression. Likewise, NSs of Guertu virus (GTV) hijack TBK1 and STAT2 into IBs and filamentous structures (FSs) affecting the corresponding signal transduction.