Host Responses and Regulation by NFκB Signaling in the Liver and Liver Epithelial Cells Infected with A Novel Tick-borne Bunyavirus

Sun, Qiyu; Jin, Cong; Zhu, Lili; Liang, Mifang; Li, Chuan; Cardona, Carol J.; Li, Dexin; Xing, Zheng

doi:10.1038/srep11816

Cited by 23 publications

(29 citation statements)

References 41 publications

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“…Despite the high awareness within the medical community in SFTS-endemic areas, and the use of antiviral therapy such as ribavirin, the case fatality rate of SFTS is still as high as 15%, which is the same as other severe viral diseases including viral hemorrhagic fevers (15). In SFTS, inflammatory cytokine storms (11,(16)(17)(18)(19) as well as impairment of immune responses including innate immunity (14,(20)(21)(22)(23)(24)(25), antiviral T cell function (26), and antiviral humoral responses (27) have important roles in the pathogenic progress of lethal infections. Immune impairment and high viral loads are also characteristics of several other viral hemorrhagic fevers (28), but these diseases differ in terms of pathology and pathogenesis, about which little is known for SFTS.…”

Section: Introductionmentioning

confidence: 99%

Severe fever with thrombocytopenia syndrome virus targets B cells in lethal human infections

Suzuki

Sato

Sano

et al. 2020

Journal of Clinical Investigation

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jp (HS). in vitro experiments using PBMCs and cell lines. MK conducted EM analysis and acquired EM images. SM, SF, TY, M. Shimojima, and M. Saijo provided reagents for histopathological and virological assays. TS wrote the original draft of the manuscript. All authors contributed to reviewing and editing the manuscript. SM and M. Saijo supervised the study and supported analyses. TS and HH supervised the study.

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Section: Introductionmentioning

confidence: 99%

Severe fever with thrombocytopenia syndrome virus targets B cells in lethal human infections

Suzuki

Sato

Sano

et al. 2020

Journal of Clinical Investigation

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“…Moreover, it was also shown that the expression of SFTSV NSs induced NF-κB promoter activity in the liver hepatocellular carcinoma cell line, HepG2 [125]. In contrast, studies using HeLa cells derived from human cervical cancer and in 293T, derived from human embryonic kidney cells, showed inhibition of NF-κB activity by SFTSV NSs suggesting that NF-κB activation by SFTSV NSs might be cell-type or tissue specific [125]. Strikingly, it has been shown that pre-treatment of THP-1 cells with an NF-κB inhibitor, 6-amino-4-(phenoxyphenyl-ethylamino)quinozoline, prior to infection with SFTSV, reduced viral titers [46].…”

Section: Pro-inflammatory Activation and Suppression By Banyangvirus Nssmentioning

confidence: 97%

“…One group demonstrated transient NF-κB activation during SFTSV infection in human leukemia monocytic cell line, THP-1 [46]. Moreover, it was also shown that the expression of SFTSV NSs induced NF-κB promoter activity in the liver hepatocellular carcinoma cell line, HepG2 [125]. In contrast, studies using HeLa cells derived from human cervical cancer and in 293T, derived from human embryonic kidney cells, showed inhibition of NF-κB activity by SFTSV NSs suggesting that NF-κB activation by SFTSV NSs might be cell-type or tissue specific [125].…”

Section: Pro-inflammatory Activation and Suppression By Banyangvirus Nssmentioning

confidence: 99%

“…Rabies virus disturbs stability of TPL2/p105/ABIN2 complex via binding to another host interaction partner participating in this complex, RelAp43 (spliced variant of RelA), leading to the suppression of target gene expression [123,124]. In addition to the role of the banyangvirus NSs protein in evasion of the innate immune response, SFTSV NSs is considered to be involved in the induction of the pro-inflammatory response via activation of NF-κB [46,125]. One group demonstrated transient NF-κB activation during SFTSV infection in human leukemia monocytic cell line, THP-1 [46].…”

Section: Pro-inflammatory Activation and Suppression By Banyangvirus Nssmentioning

confidence: 99%

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Immune Modulation and Immune-Mediated Pathogenesis of Emerging Tickborne Banyangviruses

2019

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In the last decade, the emergence of several, novel tickborne viruses have caused significant disease in humans. Of interest are the tickborne banyangviruses: Severe fever with thrombocytopenia syndrome virus (SFTSV), Heartland virus (HRTV), and Guertu virus (GTV). SFTSV and HRTV infection in humans cause viral hemorrhagic fever-like disease leading to mortality rates ranging from 6–30% of the cases. The systemic inflammatory response syndrome (SIRS) associated with SFTSV infection is hypothesized to contribute significantly to pathology seen in patients. Despite the severe disease caused by HRTV and SFTSV, there are no approved therapeutics or vaccines. Investigation of the immune response during and following infection is critical to the generation of fully protective vaccines and/or supportive treatments, and overall understanding of viral immune evasion mechanisms may aid in the development of a new class of therapeutics.

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“…Our previous studies showed that SFTSV-infected human liver epithelial cells HepG2 and unique cytoplasmic IBs were formed by NSs of SFTSV (21,23,33,37). We have further discovered that the IBs were constructed based on lipid droplets and that NSs was the only viral protein that targets lipid droplets.…”

Section: Up-regulation Of Synaptogyrin-2 In Sftsv-infected Hepg2mentioning

confidence: 97%

Synaptogyrin-2 Promotes Replication of a Novel Tick-borne Bunyavirus through Interacting with Viral Nonstructural Protein NSs

Sun

Zhang

et al. 2016

Journal of Biological Chemistry

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Synaptogyrin-2 is a non-neuronal member of the synaptogyrin family involved in synaptic vesicle biogenesis and trafficking. Little is known about the function of synaptogyrin-2. Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease characterized by high fever, thrombocytopenia, and leukocytopenia with high mortality, caused by a novel tick-borne phlebovirus in the family Bunyaviridae. Our previous studies have shown that the viral nonstructural protein NSs forms inclusion bodies (IBs) that are involved in viral immune evasion, as well as viral RNA replication. In this study, we sought to elucidate the mechanism by which NSs formed the IBs, a lipid droplet-based structure confirmed by NSs co-localization with perilipin A and adipose differentiation-related protein (ADRP). Through a high throughput screening, we identified synaptogyrin-2 to be highly up-regulated in response to SFTS bunyavirus (SFTSV) infection and to be a promoter of viral replication. We demonstrated that synaptogyrin-2 interacted with NSs and was translocated into the IBs, which were reconstructed from lipid droplets into large structures in infection. Viral RNA replication decreased, and infectious virus titers were lowered significantly when synaptogyrin-2 was silenced in specific shRNAexpressing cells, which correlated with the reduced number of the large IBs restructured from regular lipid droplets. We hypothesize that synaptogyrin-2 is essential to promoting the formation of the IBs to become virus factories for viral RNA replication through its interaction with NSs. These findings unveil the function of synaptogyrin-2 as an enhancer in viral infection. Synaptogyrin-2 (SYNGR2)2 is a tetraspan vesicle membrane protein (1-3) and a member of the synaptogyrin family. Synaptogyrin-1 and -3, abundantly present in synaptic vesicles, are believed to be involved in various aspects in the synaptic vesicle cycle, including vesicle biogenesis, exocytosis and endocytotic recycling, and neurotransmission (2, 4). They are encoded by multigene classes in mammals and evolutionarily conserved throughout the animal kingdom (5). The synaptogyrin-2 gene transcript of 1.6 kb is expressed at high levels in all tissues, except brain, encoding a protein of 224 amino acids in length (5). However, studies on synaptogyrin-2 have been limited, and the function of this protein is largely unknown.Emerging tick-borne bunyaviruses have been recognized to be a serious threat to public health and include severe fever with thrombocytopenia syndrome virus (SFTSV) (6). Since first identified in 2010 in China (7), SFTSV has caused over 3000 reported cases with mortalities ranging from 5 to 15% and has quickly spread to more than 13 provinces (8, 9). Although the symptoms of SFTS are mainly nonspecific, drastic loss of white blood cells and platelets are reported in most cases, and multiorgan failure can occur in severe cases, which usually are fatal (10, 11). SFTSV has also been isolated from patients in Korea and Japan since 2013 (12-15). The clo...

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Host Responses and Regulation by NFκB Signaling in the Liver and Liver Epithelial Cells Infected with A Novel Tick-borne Bunyavirus

Cited by 23 publications

References 41 publications

Severe fever with thrombocytopenia syndrome virus targets B cells in lethal human infections

Severe fever with thrombocytopenia syndrome virus targets B cells in lethal human infections

Immune Modulation and Immune-Mediated Pathogenesis of Emerging Tickborne Banyangviruses

Synaptogyrin-2 Promotes Replication of a Novel Tick-borne Bunyavirus through Interacting with Viral Nonstructural Protein NSs

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