Viral suppression of innate immunity via spatial isolation of TBK1/IKKε from mitochondrial antiviral platform

Abstract

For antiviral signaling mediated by retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), the recruitment of cytosolic RLRs and downstream molecules (such as TBK1 and IKKε) to mitochondrial platform is a central event that facilitates the establishment of host antiviral state. Here, we present an example of viral targeting for immune evasion through spatial isolation of TBK1/IKKε from mitochondrial antiviral platform, which was employed by severe fever with thrombocytopenia syndrome virus (SFTSV), a deadly bunyavirus emerging recently. We showed that SFTSV nonstructural protein NSs functions as the interferon (IFN) antagonist, mainly via suppressing TBK1/IKKε-IRF3 signaling. NSs mediates the formation of cytoplasmic inclusion bodies (IBs), and the blockage of IB formation impairs IFN-inhibiting activity of NSs. We next demonstrate that IBs are utilized to compartmentalize TBK1/IKKε. The compartmentalization results in spatial isolation of the kinases from mitochondria, and deprived TBK1/IKKε may participate in antiviral complex assembly, leading to the blockage of IFN induction. This study proposes a new role of viral IBs as virus-built 'jail' for imprisoning cellular factors and presents a novel and likely common mechanism of viral immune evasion through spatial isolation of critical signaling molecules from the mitochondrial antiviral platform.

Immunization with Recombinant SFTSV/NSs Protein Does Not Promote Virus Clearance in SFTSV-Infected C57BL/6J Mice

“…The nonstructural proteins of YFV, Japanese encephalitis virus, and dengue virus were usually expressed on the surface of and/ or secreted extracellular from infected cells (5,10,17,24), which could induce antiviral immunity. However, SFTSV/ NSs was expressed as cytoplasmic inclusion bodies in infected cells (15,20), which was further verified by locating NSs in SFTSV-infected DH82 cells cultured for 3 days but not secreted to their culture medium by ELISA and cell immunofluorescence test in this study (Supplementary Fig. S1; Supplementary Data are available online at www.liebertpub.com/vim).…”

“…Similar to most of viral nonstructural proteins (4,6), SFTSV/NSs was reported to be involved in suppressing the IFN expression and regulating innate immune response after SFTSV enters the host (15). It was also thought to be involved in the replication of SFTSV, as it was found to have an interaction with nucleoprotein and RNA in the infected cells (20).…”

“…Researchers have recently also found that SFTSV NSs had a similar effect on the viral multiplication, through the regulation of and escape from the host's innate immunity (15,16,20). Based on the physician's experience in clinical practice of SFTS treatment, it is unacceptable to give extrinsic IFN to SFTS patients due to the serious side effects of IFN administration, for example, severe fever, leukocytopenia, and thrombocytopenia, which are just the typical symptoms caused by SFTSV infection.…”

Suppression of type I and type III IFN signalling by NSs protein of severe fever with thrombocytopenia syndrome virus through inhibition of STAT1 phosphorylation and activation

“…Consistent with this, SFTSV NSs protein has been shown to suppress type I IFN production through the interaction with RIG-I and TRIM25, as well as IRF3 kinases TBK1 and IKKe, leading to their sequestration in virus-induced cytoplasmic subdomains separated from mitochondria (Qu et al, 2012;Ning et al, 2014;Santiago et al, 2014;Wu et al, 2014). In addition, SFTSV NSs has recently been found to perturb type I IFN signalling by interacting with STAT2, and thus retaining STAT1 and STAT2 in the cytoplasm (Ning et al, 2015).…”

“…The inability of the remaining SFTSV to augment or at least maintain the ISG-inducing activity of IFN-a1 suggested that SFTSV might antagonize IFN-a1. In contrast to previous findings (Ning et al, 2014), in our setting SFTSV was capable of In addition to representative ISGs, we also examined the expression of two pro-inflammatory cytokines IL-8 and CCL5 in infected cells. Both IL-8 and CCL5 are wellcharacterized NFkB target genes (Kunsch & Rosen, 1993;Wickremasinghe et al, 2004).…”