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Development of a novel virus-like particle-based vaccine for preventing tick-borne encephalitis virus infection

Virologica Sinica 2023年第5期38卷 767-777页

作者： jielin tang Muqing Fu Chonghui Xu Bao Xue Anqi Zhou Sijie Chen He Zhao Yuan Zhou Jizheng Chen Qi Yang Xinwen Chen Guangzhou National Laboratory Guangzhou510005China State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan430071China Guangzhou Institutes of Biomedicine and Health Chinese Academy of SciencesGuangzhou510530China GMU-GIBH Joint School of Life Sciences Guangzhou Medical UniversityGuangzhou511436China State Key Laboratory of Respiratory Disease Guangzhou Medical UniversityGuangzhou511436China

Tick-borne encephalitis virus(TBEV)is an important tick-borne pathogen that poses as a serious public health concern.The coverage and immunogenicity of the currently available vaccines against TBEV are relatively low;therefore,it is crucial to develop novel and effective vaccines against TBEV.The present study describes a novel strategy for the assembly of virus-like particles(VLPs)by co-expressing the structural(core/prM/E)and non-structural(NS2B/NS3Pro)proteins of TBEV.The efficacy of the VLPs was subsequently evaluated in C57BL/6 mice,and the resultant IgG serum could neutralize both Far-Eastern and European subtypes of TBEV.These findings indicated that the VLP-based vaccine elicited the production of cross-subtype reactive antibodies.The VLPs provided protection to mice lacking the type I interferon receptor(IFNAR^(-/-))against lethal TBEV challenge,with undetectable viral load in brain and intestinal tissues.Furthermore,the group that received the VLP vaccine did not exhibit significant pathological changes and the inflammatory factors were significantly suppressed compared to the control group.Immunization with the VLP vaccine induced the production of multiple-cytokine-producing antiviral CD4+T cells in vivo,including TNF-α^(+),IL-2^(+),and IFN-γ^(+)T cells.Altogether,the findings suggest that noninfectious VLPs can serve as a potentially safe and effective vaccine candidate against diverse subtypes of TBEV.

关键词： Tick-borne encephalitis virus(TBEV) Virus-like particle(VLP) Immunogenicity Neutralization Vaccine

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Comparison of viral propagation and drug response among SARS-CoV-2 VOCs using replicons capable of recapitulating virion assembly and release

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Virologica Sinica 2022年第5期37卷 695-703页

作者： Lingqian Tian Qiuhong Liu Rongjuan Pei Yingshan Chen Chonghui Xu jielin tang Hao Sun Kunpeng Liu Qi Yang Lei Yang Leshan Li Yongli Zhang Yuan Zhou Chao Shan Xue Hu Xinwen Chen Yun Wang State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan430071China University of Chinese Academy of Sciences Beijing100049China Department of Gastroenterology Guangzhou Women and Children's Medical CenterGuangzhou510623China Guangzhou Institutes of Biomedicine and Health Chinese Academy of SciencesGuangzhou510530China Innovation Center for Pathogen Research Guangzhou LaboratoryGuangzhou510320China

Several variants of concern(VOCs)have emerged since the WIV04 strain of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)was first isolated in January 2020.Due to mutations in the spike(S)protein,these VOCs have evolved to enhance viral infectivity and immune evasion.However,whether mutations of the other viral proteins lead to altered viral propagation and drug resistance remains obscure.The replicon is a noninfectious viral surrogate capable of recapitulating certain steps of the viral life cycle.Although several SARS-CoV-2 replicons have been developed,none of them were derived from emerging VOCs and could only recapitulate viral genome replication and subgenomic RNA(sgRNA)transcription.In this study,SARS-CoV-2 replicons derived from the WIV04 strain and two VOCs(the Beta and Delta variants)were prepared by removing the S gene from their genomes,while other structural genes remained untouched.These replicons not only recapitulate viral genome replication and sgRNA transcription but also support the assembly and release of viral-like particles,as manifested by electron microscopic assays.Thus,the S-deletion replicon could recapitulate virtually all the post-entry steps of the viral life cycle and provides a versatile tool for measuring viral intracellular propagation and screening novel antiviral drugs,including inhibitors of virion assembly and release.Through the quantification of replicon RNA released into the supernatant,we demonstrate that viral intracellular propagation and drug response to remdesivir have not yet substantially changed during the evolution of SARS-CoV-2 from the WIV04 strain to the Beta and Delta VOCs.

关键词： SARS-CoV-2 Variants of concern(VOC) Viral-like particle(VLP) Replicon Remdesivir

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Histone Deacetylase 3 Inhibitor Suppresses Hepatitis C Virus Replication by Regulating Apo-A1 and LEAP-1 Expression

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Virologica Sinica 2018年第5期33卷 418-428页

作者： Yuan Zhou Qian Wang Qi Yang jielin tang Chonghui Xu Dongwei Gai Xinwen Chen Jizheng Chen State Key Laboratory of Virology Wuhan Institute of VirologyChinese Academy of SciencesWuhan 430071China University of Chinese Academy of Sciences Beijing 100101China Jiangsu Province Key Laboratory of Human Functional Genomies Department of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjing 210029China

Histone deacetylase (HDAC) inhibitors show clinical promise for the treatment of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the effect of HDAC inhibitor treatment on hepatitis C virus (HCV)replication in Huh7 human liver cells and in a mouse model of HCV infection. Viral replication was markedly suppressed by the HDAC3 inhibitor at concentrations below 1 mmol/L, with no cellular toxicity. This was accompanied by upregulation of liver-expressed antimicrobial peptide 1 (LEAP-1) and downregulation of apolipoprotein-A1 (Apo-A1), as determined by microarray and quantitative RT-PCR analyses. Moreover, HDAC3 was found to modulate the binding of CCAAT-enhancer-binding protein a (C/EBPa), hypoxia-inducible factor 1 a (HIF1 a), and signal transducer and activator of transcription 3 (STAT3) to the LEAP-1 promoter. HDAC3 inhibitor treatment also blocked HCV replication in a mouse model of HCV infection. These results indicate that epigenetic therapy with HDAC3 inhibitor may be a potential treatment for diseases associated with HCV infection such as HCC.

关键词： Hepatitis C virus (HCV) HDAC3 Apolipoprotein-A1 (Apo-A1) LEAP-1 Hepatocellular carcinoma Viral replication

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Histone deacetylase 4 inhibits NF-κB activation by facilitating IκBα sumoylation

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Journal of Molecular Cell Biology 2020年第12期12卷 933-945页

作者： Qi Yang jielin tang Chonghui Xu He Zhao Yuan Zhou Yanyi Wang Min Yang Xinwen Chen Jizheng Chen Department of Gastroenterology Guangzhou Women and Children's Medical CenterGuangzhou 510623China State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China University of Chinese Academy of Sciences Beijing 100049China Guangzhou Institutes of Biomedicine and Health Chinese Academy of SciencesGuangzhou 510530China

Protein modification by small ubiquitin-like modifier(SUMO)is an important regulatory mechanism for multiple cellular pro-cesses.Although the canonical pathway involving the ubiquitylation or phosphorylation of IκBα has been well characterized,little is known about the sumoylation of IkBa in the control of NF-κB activity.Here,we find that histone deacetylase 4(HDAC4)negatively regulates tumor necrosis factor-alpha-or lipopolysaccharide-triggered NF-κB activation.HDAC4 belongs to the SUMO E3 ligase family and can directly sumoylate IκBα.The cytoplasm location of HDAC4 is essential for IκBαsumoylation.The Cys292 of HDAC4 is a key site for its SUMO E3 ligase activity.The sumoylation of IkBc prevents its polyubiquitination and degradation be-cause these two modifications occur both at the Lys21.Our findings reveal a previously undiscovered role for HDAC4 in the inflammatory response as a SUMO E3 ligase for IκBαsumoylation.Our work provides insight into mechanisms ensuring optimal mediation of the NF-κB pathway.

关键词： histone deacetylase 4 sumoylation IκBα NF-κB SUMO E3 ligase

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数字经济对我国区域低碳发展的影响及空间溢出效应研究

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重庆三峡学院学报 2024年第2期40卷 29-42页

作者：张翠菊汤杰霖重庆工商大学经济学院重庆400067

数字经济的发展为顺利实现“双碳”目标提供了全新的路径。基于2011—2019年省域面板数据,探寻区域数字经济发展及碳排放水平的空间分布特征,运用空间杜宾模型分析数字经济发展对碳排放的影响及其空间溢出性。研究结果显示:(1)数字经济... 详细信息

数字经济的发展为顺利实现“双碳”目标提供了全新的路径。基于2011—2019年省域面板数据,探寻区域数字经济发展及碳排放水平的空间分布特征,运用空间杜宾模型分析数字经济发展对碳排放的影响及其空间溢出性。研究结果显示:(1)数字经济的发展表现出两极极度分化的趋势,并呈现出向经济圈集聚的空间特征。(2)碳排放水平的发展呈现出南高北低的态势;在碳减排形势上,中西部地区比东部地区更为严峻。(3)数字经济的发展不仅显著降低了区域内的碳排放水平,而且对周边区域的碳减排产生了积极的促进作用。

关键词：数字经济碳排放空间杜宾模型空间溢出效应

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Host HDAC4 regulates the antiviral response by inhibiting the phosphorylation of IRF3

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Journal of Molecular Cell Biology 2019年第2期11卷 158-169页

作者： Qi Yang jielin tang Rongjuan Pei XiaoXiao Gao Jing Guo Chonghui Xu Yun Wang QianWang Chunchen Wu Yuan Zhou Xue Hu He Zhao Yanyi Wang Xinwen Chen Jizheng Chen State Key Laboratory of Virology Wuhan Institute of Virology Chinese Academy of Sciences Wuhan 430071 China University of Chinese Academy of Sciences Beijing 100049 China Key Laboratory of Human Functional Genomics of Jiangsu Province School of Basic Medical Science Nanjing Medical University Nanjing 210093 China

Class II HDACs, such as HDAC4, are critical regulators of the immune response in various immune cells;however, its role in innate immunity remains largely unknown.Here, we report that the overexpression of HDAC4 suppresses the production of type I interferons triggered by pattern-recognition receptors (PRRs). HDAC4 repressed the translocation of transcription factor IRF3 to the nucleus, thereby decreasing IRF3-mediated IFN-β expression. In particular, we also determined that HDAC4 can be phosphorylated and simultaneously block the phosphorylation of IRF3 at Ser386 and Ser396 by TBK1 and IKKε, respectively, by interacting with the kinase domain of TBK1 and IKKε. Furthermore, IFN-β may stimulate the expression of HDAC4. Our findings suggest that HDAC4 acts as a regulator of PRR signaling and is a novel mechanism of negative feedback regulation for preventing an overreactive innate immune response.

关键词： HDAC4 antiviral response IRF3 TBK1 IKKε

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Functions of human histone deacetylase 5(HDAC5) in the innate immune signaling pathways

Functions of human histone deacetylase 5(HDAC5) in the innat...

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第十三届全国免疫学学术大会

作者： Chonghui Xu jielin tang Qi Yang Jizheng Chen Xinwen Chen State Key Laboratory of Virology Wuhan Institute of Virology Chinese Academy of Sciences University of Chinese Academy of Sciences

As a member of the class IIa family of histone deacetylases, the histone deacetylase 5(HDAC5) is known to be a critical transcriptional regulator and linked to prominent human diseases, including cardiac diseases and tumorigenesis.Here we find that knockdown of HDAC5 in human cell lines and bone marrow-derived macrophages(BMDMs) from mice results in attenuated phosphorylation of p65 at Ser536.Consistently, the levels of inflammation-related cytokines, such as TNF-α and IL-6, obviously reduced in cell culture supernatant after lipopolysaccharide(LPS) stimulation compared to the wild-type controls.In summary, our findings suggest that HDAC5 acts as a new regulator of anti-inflammatory responses.

关键词： histone deacetylase 5 innate immune anti-inflammatory response

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Functional characterization of the human histone deacetylase 3(HDAC3) in the innate immune signaling pathways

Functional characterization of the human histone deacetylase...

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第十三届全国免疫学学术大会

作者： jielin tang Qi Yang Chonghui Xu He Zhao Dongwei Gai Jizheng Chen Xinwen Chen State Key Laboratory of Virology Wuhan Institute of Virology Chinese Academy of Sciences University of Chinese Academy of Sciences

The histone deacetylase 3(HDAC3) has high expression in terminally differentiated tissue;however, its role in innate immunity remains largely unknown. Here, we report that HDAC3 act as a positive regulator, depending on its’ deacetyl ability, regulated the activation of type I interferon mediated by double-stranded RNA or DNA by targeting TBK1. HDAC3-deficient mice reduced the production of type I interferon and were more susceptibility to lethal viral infection compared to wild-type. HDAC3 directly regulated Lys K241 and K692 deacetylation of TBK1, while deacetylation of these sites was critical for the kinase activity of TBK1. Therefore, our work provided molecular insights into the mechanisms by which HDAC3 directly maintained the deacetylation status of TBK1 and enhanced its kinase activity.

关键词： HDAC3 Innate immune response TBK1 deacetylation

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磷酸三甲苯酯对秀丽隐杆线虫的生殖毒性及机制

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环境与职业医学 2022年第5期39卷 532-538页

作者：唐洁琳张红丹周沁宇李佳忆王彤张娟东南大学公共卫生学院/环境医学工程教育部重点实验室江苏南京210009

[背景]磷酸三甲苯酯(TCP)主要用作阻燃剂。研究证实其具有细胞毒性和神经毒性,但对于其生殖毒性尚不明确。[目的]研究TCP亚急性暴露对秀丽隐杆线虫的生殖毒性以及潜在机制。[方法]将秀丽隐杆线虫分别暴露于溶剂对照以及0.1、1、10、100... 详细信息

[背景]磷酸三甲苯酯(TCP)主要用作阻燃剂。研究证实其具有细胞毒性和神经毒性,但对于其生殖毒性尚不明确。[目的]研究TCP亚急性暴露对秀丽隐杆线虫的生殖毒性以及潜在机制。[方法]将秀丽隐杆线虫分别暴露于溶剂对照以及0.1、1、10、100、1 000μg·L^(-1)TCP的培养基72 h,检测后代数目和子宫内受精卵的数量,评价生殖能力;检测总生殖细胞数和生殖腺臂相对面积,评价生殖腺发育;检测体长和体宽,评价生长发育;检测秀丽隐杆线虫体内活性氧(ROS)水平、超氧化物歧化酶(SOD)活性,利用实时荧光定量PCR检测N2线虫线粒体活性氧代谢基因(mev-1和gas-1)的表达,评价氧化应激水平。WS1433转基因线虫和野生型线虫N2分别暴露于溶剂对照或TCP(0.1、1、10、100、1 000μg·L^(-1))后,检测WS1433转基因线虫生殖细胞DNA损伤情况,实时荧光定量PCR检测N2线虫DNA损伤相关基因(hus-1、clk-2、cep-1和egl-1)的相对表达,评价TCP暴露对秀丽隐杆线虫遗传损伤的影响。[结果]与溶剂对照组相比(217.00±12.20),100μg·L^(-1)和1 000μg·L^(-1)TCP组N2线虫的后代数目减少(170.80±11.51、169.60±10.52,P <0.05)。与溶剂对照组相比(18.43±1.69),100μg·L^(-1)和1 000μg·L^(-1)TCP组N2线虫的子宫内受精卵数目减少(13.47±0.81、11.95±0.90,P <0.05)。与溶剂对照组相比(312.46±77.4),100μg·L^(-1)和1 000μg·L^(-1)TCP组N2线虫的总生殖细胞数减少(281.80±12.98、273.50±8.53,P <0.05)。与溶剂对照组相比,100μg·L^(-1)和1 000μg·L^(-1)TCP组N2线虫的生殖腺相对面积分别减少13.83%、17.25%(P <0.05)。与溶剂对照组相比[(1 058.10±80.12)μm、(78.21±14.69)μm],100μg·L^(-1)和1 000μg·L^(-1)TCP组N2线虫的体长、体宽均减少(P <0.05)。与溶剂对照组相比,10、100和1 000μg·L^(-1)TCP组线虫体内ROS相对荧光强度增加(为107.60%±1.02%、105.90%±1.40%、106.40%±1.85%,P <0.05),SOD活性分别降低(降低20.66%、15.88%、16.44%,P <0.05)。与溶剂对照组相比(1.3±1.3),100和1 000μg·L^(-1)TCP组WS1433线虫DNA损伤的生殖细胞数目上升(2.4±0.3、2.7±0.3,P <0.05);10、100和1 000μg·L^(-1)TCP组N2线虫mev-1和gas-1基因表达降低(P <0.05);0.1~1 000μg·L^(-1)TCP组线虫hus-1基因表达增加(P <0.05);100和1 000μg·L^(-1)TCP组线虫clk-2和egl-1基因表达增加(P <0.05);1、10和100μg·L^(-1)TCP组线虫cep-1基因表达增加(P <0.05)。[结论] TCP可能通过氧化应激和生殖细胞DNA损伤对线虫造成生殖损伤。

关键词：有机磷酸酯秀丽隐杆线虫生殖毒性 DNA损伤氧化应激

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Desulfuromonas alkenivorans S-7联合稻壳处理酸性重金属废水

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煤炭学报 2019年第9期44卷 2851-2858页

作者：佘臣杰唐婕琳何环张朦童丽唐俊陶秀祥中国矿业大学化工学院江苏徐州221116 中国矿业大学煤炭加工与高效洁净利用教育部重点实验室江苏徐州221116 中国矿业大学安全工程学院江苏徐州221116

为了研究硫酸盐还原菌和稻壳联合生物反应器在重金属废水处理中作用及机理。利用实验室前期分离鉴定的硫酸盐还原菌 Desulfuromonas alkenivorans S-7联合填充稻壳柱式生物反应器处理人工合成酸性重金属(Fe 3+,Mn 2+,Cr 6+)废水。比较... 详细信息

为了研究硫酸盐还原菌和稻壳联合生物反应器在重金属废水处理中作用及机理。利用实验室前期分离鉴定的硫酸盐还原菌 Desulfuromonas alkenivorans S-7联合填充稻壳柱式生物反应器处理人工合成酸性重金属(Fe 3+,Mn 2+,Cr 6+)废水。比较了废水处理过程中理化特性(pH, E h , E c )及3种重金属离子变化规律,并利用FT-IR光谱仪分析了微生物和稻壳联合处理作用下重金属离子去除特性。研究结果表明:S-7能够明显提高酸性废水的pH,20 d后pH 最终稳定在6.20左右,也能使反应体系维持在较高的还原环境并降低体系的电导率。S-7菌株对3种代表性离子都有一定的处理效果,对Fe,Mn,Cr三种金属离子的去除效率分别为Fe>Mn>Cr。反应器处理前期废水中离子的去除速率较快,后期由于离子共存对废水处理的影响使废水中金属离子浓度趋于平衡,出现动态制约平衡,S-7菌株对3种重金属离子的去除机制可能存在差异。处理后期由于Cr 6+浓度上升明显,增大了SRB反应器中的重金属含量,明显影响SRB反应器的稳定性能;稻壳填充对S-7菌株生长能够稳定维持SRB反应器的厌氧环境,并且稻壳对金属离子去除也存在一定程度的物理吸附作用。FT-IR分析表明:S-7菌体处理废水时会吸附Fe,Mn,Cr离子,其中羟基、胺基、酰胺基及羧基是发生吸附作用重要的官能团;稻壳在处理重金属废水前后,稻壳的Si—O—Si和羰基在处理重金属废水中可能发挥了作用。

关键词：硫酸盐还原菌生物反应器重金属离子傅里叶红外光谱(FT-IR)

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