Suppression of the Interferon and NF-κB Responses by Severe Fever with Thrombocytopenia Syndrome Virus

Abstract

e Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease characterized by high fever, thrombocytopenia, multiorgan dysfunction, and a high fatality rate between 12 and 30%. It is caused by SFTS virus (SFTSV), a novel Phlebovirus in family Bunyaviridae. Although the viral pathogenesis remains largely unknown, hemopoietic cells appear to be targeted by the virus. In this study we report that human monocytes were susceptible to SFTSV, which replicated efficiently, as shown by an immunofluorescence assay and real-time reverse transcription-PCR. We examined host responses in the infected cells and found that antiviral interferon (IFN) and IFN-inducible proteins were induced upon infection. However, our data also indicated that downregulation of key molecules such as mitochondrial antiviral signaling protein (MAVS) or weakened activation of interferon regulatory factor (IRF) and NF-B responses may contribute to a restricted innate immunity against the infection. NSs, the nonstructural protein encoded by the S segment, suppressed the beta interferon (IFN-␤) and NF-B promoter activities, although NF-B activation appears to facilitate SFTSV replication in human monocytes. NSs was found to be associated with TBK1 and may inhibit the activation of downstream IRF and NF-B signaling through this interaction. Interestingly, we demonstrated that the nucleoprotein (N), also encoded by the S segment, exhibited a suppressive effect on the activation of IFN-␤ and NF-B signaling as well. Infected monocytes, mainly intact and free of apoptosis, may likely be implicated in persistent viral infection, spreading the virus to the circulation and causing primary viremia. Our findings provide the first evidence in dissecting the host responses in monocytes and understanding viral pathogenesis in humans infected with a novel deadly Bunyavirus.

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

“…Thus, SFTSV NSs preferentially suppressed IRF3 but not NFkB activity in our setting. These results were at odds with a previous report (Qu et al, 2012), but might be more compatible with the overproduction of NFkB-induced cytokines in SFTSVinfected cells (Jin et al, 2015). Further studies are required to determine whether NFkB is activated by SFTSV.…”

“…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).…”

“…During the course of SFTSV infection in humans, IFNs are almost undetectable in the blood (Qu et al, 2012), indicating the suppression of IFN production. 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).…”

“…Although SFTSV NSs has been shown to inhibit both NFkB and IRF3 transcription factors (Qu et al, 2012), we noted the upregulated expression of many NFkB-regulated cytokines such as IL-6, IL-8 and TNF-a in humans and primates infected with SFTSV (Deng et al, 2012;Sun et al, 2012;Jin et al, 2015). To resolve this discrepancy, we compared the impact of NSs expression on Sendai virus (SENV)-induced activation of IFN-b promoter and canonical kB elements.…”

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

“…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.…”