HTNV

HTNV
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  • 文章类型: Journal Article
    汉坦病毒(HTNV)是主要的公共卫生问题,因为它能够在欧亚大陆引起肾综合征出血热(HFRS)。HFRS的症状包括发烧,出血,免疫功能障碍和肾功能损害,严重的病例可能是致命的。T细胞介导的适应性免疫应答在对抗HTNV感染中起关键作用。然而,我们对疾病进展中HTNV和T细胞相互作用的理解有限.在这项研究中,我们发现人类CD4+T细胞可以直接感染HTNV,从而促进病毒复制和生产。此外,T细胞免疫球蛋白和粘蛋白1(TIM-1)参与了HTNV感染JurkatT细胞的过程,并进一步观察到HTNV通过网格蛋白依赖性胞吞途径进入JurkatT细胞。这些发现不仅肯定了人类CD4T淋巴细胞对HTNV的敏感性,而且还阐明了病毒的嗜性。我们的研究阐明了病毒感染过程与免疫系统之间相互作用的模式。严重的,这项研究为HTNV的发病机制和抗病毒研究提供了新的见解。
    Hantaan virus (HTNV) is a major public health concern due to its ability to cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia. Symptoms of HFRS include fever, hemorrhage, immune dysfunction and renal impairment, and severe cases can be fatal. T cell-mediated adaptive immune responses play a pivotal role in countering HTNV infection. However, our understanding of HTNV and T cell interactions in the disease progression is limited. In this study, we found that human CD4+ T cells can be directly infected with HTNV, thereby facilitating viral replication and production. Additionally, T-cell immunoglobulin and mucin 1 (TIM-1) participated in the process of HTNV infection of Jurkat T cells, and further observed that HTNV enters Jurkat T cells via the clathrin-dependent endocytosis pathway. These findings not only affirm the susceptibility of human CD4+ T lymphocytes to HTNV but also shed light on the viral tropism. Our research elucidates a mode of the interaction between the virus infection process and the immune system. Critically, this study provides new insights into the pathogenesis of HTNV and the implications for antiviral research.
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  • 文章类型: Journal Article
    由于肾综合征出血热(HFRS)在全球范围内复发,更多的注意力集中在这种危险的疾病上。在中国和韩国,唯一可用的疫苗是针对汉坦病毒(HTNV)或首尔病毒(SEOV)的病毒灭活疫苗,但是这些疫苗的功效和安全性不足。因此,重要的是要开发更安全,更有效的新疫苗,以中和和调节HFRS患病率高的地区。我们采用生物信息学方法基于HTNV和SEOV膜中蛋白质共有序列的保守区域设计了重组蛋白质疫苗。S2果蝇表达系统用于增强蛋白质表达,溶解性和免疫原性。HTNV和SEOV的Gn和Gc蛋白成功表达后,小鼠免疫,和体液免疫,细胞免疫,在小鼠模型中系统评估了HFRS通用亚单位疫苗的体内保护作用。这些结果表明HFRS亚单位疫苗产生的结合和中和抗体水平升高,特别是IgG1,与传统的灭活HFRS疫苗相比。此外,免疫小鼠的脾细胞有效分泌IFN-r和IL-4细胞因子。此外,HTNV-Gc蛋白疫苗成功保护乳鼠免受HTNV感染并刺激GC反应。在这项研究中,研究了一种新的科学方法来开发一种通用的HFRS亚单位蛋白疫苗,该疫苗能够在小鼠中产生有效的体液和细胞免疫。结果表明,该疫苗可能是预防人类HFRS的有希望的候选疫苗。
    Due to the global resurgence of hemorrhagic fever with renal syndrome (HFRS), more attention is being focused on this dangerous illness. In China and Korea, the only vaccines available are the virus-inactivated vaccine against Hantaan virus (HTNV) or Seoul virus (SEOV), but their efficacy and safety are inadequate. Therefore, it is important to develop new vaccines that are safer and more efficient to neutralize and regulate areas with a high prevalence of HFRS. We employed bioinformatics methods to design a recombinant protein vaccine based on conserved regions of protein consensus sequences in HTNV and SEOV membranes. The S2 Drosophila expression system was utilized to enhance protein expression, solubility and immunogenicity. After the Gn and Gc proteins of HTNV and SEOV were successfully expressed, mice were immunized, and the humoral immunity, cellular immunity, and in vivo protection of the HFRS universal subunit vaccine were systematically evaluated in mouse models. These results indicated that the HFRS subunit vaccine generated elevated levels of binding and neutralizing antibodies, particularly IgG1, compared to that of the traditional inactivated HFRS vaccine. Additionally, the spleen cells of immunized mice secreted IFN-r and IL-4 cytokines effectively. Moreover, the HTNV-Gc protein vaccine successfully protected suckling mice from HTNV infection and stimulated GC responses. In this research, a new scientific approach is investigated to develop a universal HFRS subunit protein vaccine that is capable of producing effective humoral and cellular immunity in mice. The results suggest that this vaccine could be a promising candidate for preventing HFRS in humans.
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  • 文章类型: Journal Article
    Orthohantaviruses, members of the Orthohantavirus genus of Hantaviridae family of the Bunyavirales order, are enveloped, negative-sense, single-stranded, tripartite RNA viruses. They are emerging zoonotic pathogens carried by small mammals including rodents, moles, shrews, and bats and are the etiologic agents of hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) among humans. With the characteristics of low biological risk but strong operability, a variety of pseudotyped viruses have been constructed as alternatives to authentic orthohantaviruses to help delineate the roles of host factors in viral entry and other virus-host interactions, to assist in deciphering mechanisms of immune response and correlates of protection, to enhance our understanding of viral antigenic property, to characterize viral entry inhibitors, and to be developed as vaccines. In this chapter, we will discuss the general property of orthohantavirus, construction of pseudotyped orthohantaviruses based on different packaging systems, and their current applications.
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  • 文章类型: Journal Article
    未经证实:汉坦病毒(HTNV)可引起肾综合征出血热(HFRS)患者的内皮损伤。由病毒感染引起的CD8+T细胞的旁观者激活已被证明参与宿主损伤,但在HTNV感染期间尚不清楚。该项目旨在研究旁观者激活的CD8T细胞反应在HTNV感染中的作用。
    UNASSIGNED:建立体外感染模型,以模拟HFRS患者的内皮损伤。流式细胞术检测四聚体+CD8+T细胞和人脐静脉内皮细胞(HUVECs)标志物的表达。采用酶联免疫吸附试验(ELISA)试剂盒检测血清和血清中白细胞介素-15(IL-15)水平。流式细胞术和Westernblot分别检测HUVECs中MICA的表达。通过细胞毒性测定和抗体阻断测定评估CD8+T细胞的细胞毒性。
    未经证实:HFRS患者HTNV感染后,EBV或CMV特异性CD8+T细胞被旁观者激活。体外感染HTNV的HUVECs可产生高水平的IL-15,IL-15与疾病严重程度和旁观者激活的CD8T细胞上NKG2D的表达呈正相关。此外,IL-15的升高可诱导CD122(IL-15Rβ)NKG2DEBV/CMV特异性CD8T细胞的活化。IL-15Rα和NKG2D配体的表达在HTNV感染的HUVEC上上调。旁观者激活的CD8+T细胞可以对HTNV感染的HUVECs发挥细胞毒性作用,IL-15刺激可以增强,NKG2D抗体可以阻断。
    未经证实:IL-15通过NKG2D诱导旁观者激活CD8+T细胞,可能介导HFRS患者HTNV感染期间的内皮损伤。
    Hantaan virus (HTNV) can cause endothelium injury in hemorrhagic fever with renal syndrome (HFRS) patients. Bystander activation of CD8+ T cells by virus infection has been shown that was involved in host injury, but it is unclear during HTNV infection. This project aimed to study the effect of bystander-activated CD8+ T cell responses in HTNV infection.
    The in vitro infection model was established to imitate the injury of endothelium in HFRS patients. Flow cytometry was performed to detect the expression of markers of tetramer+ CD8+ T cells and human umbilical vein endothelial cells (HUVECs). The levels of interleukin-15 (IL-15) in serum and supermanant were detected using ELISA kit. The expression of MICA of HUVECs was respectively determined by flow cytometry and western blot. The cytotoxicity of CD8+ T cells was assessed through the cytotoxicity assay and antibody blocking assay.
    EBV or CMV-specific CD8+ T cells were bystander activated after HTNV infection in HFRS patients. HTNV-infected HUVECs in vitro could produce high levels of IL-15, which was positively correlated with disease severity and the expression of NKG2D on bystander-activated CD8+ T cells. Moreover, the elevated IL-15 could induce activation of CD122 (IL-15Rβ)+NKG2D+ EBV/CMV-specific CD8+ T cells. The expression of IL-15Rα and ligand for NKG2D were upregulated on HTNV-infected HUVECs. Bystander-activated CD8+ T cells could exert cytotoxicity effects against HTNV-infected HUVECs, which could be enhanced by IL-15 stimulation and blocked by NKG2D antibody.
    IL-15 induced bystander activation of CD8+ T cells through NKG2D, which may mediate endothelium injury during HTNV infection in HFRS patients.
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  • 文章类型: Journal Article
    汉坦病毒(HTNV)感染主要在亚洲引起肾综合征出血热(HFRS)的流行。粘膜相关不变T(MAIT)细胞是已知在病毒感染期间在先天宿主防御中起重要作用的先天样T淋巴细胞。然而,它们在HTNV感染过程中的作用和表型尚未被研究。我们基于scRNA-seq数据结合流式细胞术数据表征了来自HFRS患者的CD8+MAIT细胞。我们发现HTNV感染引起外周血中CD8+MAIT细胞的丢失和活化,与疾病严重程度相关。CD8MAIT细胞中颗粒酶B和IFN-γ的产生以及内皮细胞中HTNV复制的限制表明CD8MAIT细胞具有抗病毒特性。此外,HTNV或HTNV暴露的单核细胞对MAIT细胞的体外感染表明,MAIT细胞的激活是IL-18介导的。总之,这项研究确定,第一次,MAIT细胞的基因表达谱,为HTNV感染期间MAIT细胞的激活提供了潜在的分子机制,并提示MAIT细胞在HFRS中具有潜在的抗病毒作用。
    Hantaan virus (HTNV) infection causes an epidemic of hemorrhagic fever with renal syndrome (HFRS) mainly in Asia. Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes known to play an important role in innate host defense during virus infection. However, their roles and phenotypes during HTNV infection have not yet been explored. We characterized CD8+MAIT cells from HFRS patients based on scRNA-seq data combined with flow cytometry data. We showed that HTNV infection caused the loss and activation of CD8+MAIT cells in the peripheral blood, which were correlated with disease severity. The production of granzyme B and IFN-γ from CD8+MAIT cells and the limitation of HTNV replication in endothelia cells indicated the anti-viral property of CD8+MAIT cells. In addition, in vitro infection of MAIT cells by HTNV or HTNV-exposed monocytes showed that the activation of MAIT cells was IL-18 mediated. In conclusion, this study identified, for the first time, gene expression profiles of MAIT cells, provided underlying molecular mechanisms for activation of MAIT cells during HTNV infection, and suggested a potential anti-viral role of MAIT cells in HFRS.
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  • 文章类型: Journal Article
    汉坦病毒(HTNV)感染主要在亚洲引起肾综合征出血热(HFRS)的流行。众所周知,T细胞介导抗病毒免疫应答。尽管以前的研究表明,双阳性T(DPT)细胞,一小部分T淋巴细胞,参与病毒感染期间的适应性免疫反应,它们在HTNV感染中的动力学变化和作用尚未被探索。在这项研究中,我们基于流式细胞术数据和scRNA-seq数据对HFRS患者的DPT细胞进行了表征.我们发现HTNV感染引起外周血中DPT细胞的上调,与疾病分期相关。scRNA-seq数据聚集了DPT细胞,解开他们的基因表达谱,并估计了这些细胞的排序。来自DPT细胞的颗粒酶B和CD107a的产生以及丰富的TCR分布表明DPT细胞的抗病毒特性。总之,这项研究确定,第一次,HFRS患者外周血中DPT细胞的积累,表明这些DPT细胞属于CD8T细胞谱系。DPT细胞与细胞毒性T细胞(CTL)具有相似的特征,并在HFRS中发挥抗病毒作用。
    Hantaan virus (HTNV) infection causes an epidemic of hemorrhagic fever with renal syndrome (HFRS) mainly in Asia. It is well known that T cells mediated anti-viral immune response. Although previous studies showed that double positive T (DP T) cells, a little portion of T lymphocytes, were involved in adaptive immune response during virus infection, their kinetic changes and roles in HTNV infection have not yet been explored. In this study, we characterized DP T cells from HFRS patients based on flow cytometry data combined with scRNA-seq data. We showed that HTNV infection caused the upregulation of DP T cells in the peripheral blood, which were correlated with disease stage. The scRNA-seq data clustered DP T cells, unraveled their gene expression profile, and estimated the ordering of these cells. The production of granzyme B and CD107a from DP T cells and the abundant TCR distribution indicated the anti-viral property of DP T cells. In conclusion, this study identified, for the first time, an accumulation of DP T cells in the peripheral blood of HFRS patients and suggested these DP T cells belonging to CD8+T cells lineage. The DP T cells shared the similar characteristics with cytotoxic T cells (CTL) and exerted an anti-viral role in HFRS.
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  • 文章类型: Journal Article
    汉坦病毒(HTNV)感染人类并引起肾综合征出血热(HFRS)。完善的HFRS动物模型的开发可以加速候选疫苗和治疗剂的测试,并为研究HFRS的发病机理提供有用的工具。因为NLRC3具有多种免疫调节作用,我们研究了Nlrc3-/-小鼠对HTNV感染的敏感性,以建立新的HFRS模型。Nlrc3-/-小鼠出现体重减轻,肾出血,HTNV感染后的小管扩张,概括了人类HFRS的许多临床症状。此外,感染的Nlrc3-/-小鼠在血清中显示出更高的病毒载量,脾,脾和肾脏比野生型C57BL/6(WT)小鼠,与WT小鼠相比,其中一些表现出更多的血液系统疾病和多个器官内明显的病理变化。我们的结果确定,HTNV感染的Nlrc3-/-小鼠可以发展类似HFRS患者的临床症状和病理变化,为研究候选疫苗和疗法的发病机理和测试提供了新的模型。
    Hantaan virus (HTNV) infects humans and causes hemorrhagic fever with renal syndrome (HFRS). The development of well-characterized animal models of HFRS could accelerate the testing of vaccine candidates and therapeutic agents and provide a useful tool for studying the pathogenesis of HFRS. Because NLRC3 has multiple immunoregulatory roles, we investigated the susceptibility of Nlrc3-/- mice to HTNV infection in order to establish a new model of HFRS. Nlrc3-/- mice developed weight loss, renal hemorrhage, and tubule dilation after HTNV infection, recapitulating many clinical symptoms of human HFRS. Moreover, infected Nlrc3-/- mice showed higher viral loads in serum, spleen, and kidney than wild type C57BL/6 (WT) mice, and some of them manifested more hematological disorders and significant pathological changes within multiple organs than WT mice. Our results identify that HTNV infected Nlrc3-/- mice can develop clinical symptoms and pathological changes resembling patients with HFRS, suggesting a new model for studying the pathogenesis and testing of candidate vaccines and therapeutics.
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  • 文章类型: Journal Article
    肾综合征出血热(HFRS)是由汉坦病毒(HTNV)引起的具有流行潜力的区域性传染病。红细胞(RBC)是外周血的主要成分。然而,在HTNV感染期间RBC的病理变化和潜在机制仍不清楚.因此,本研究旨在探讨HFRS患者外周血中红细胞的变化。我们从HFRS患者中分离PBMC并进行单细胞RNA测序。结果表明,HFRS外周血中的红细胞簇可以根据其细胞成分分类为有核红细胞(NRBC)。基因表达谱和细胞表面标记。此外,结果表明,外周血中NRBC计数越高,病情越严重。此外,分析了与红细胞相关的血液学指标,结果表明叶酸途径的损害可能是NRBC存在的可能原因。这项研究,首次显示HFRS患者外周血中NRBC的存在与疾病严重程度相关。这也是第一项表明HTNV病毒感染阻碍RBC成熟的研究。因此,这项工作为HTNV感染期间红细胞的作用和病理变化提供了进一步的见解。
    Hemorrhagic fever with renal syndrome (HFRS) is a regional infectious disease of epidemic potential caused by the Hantaan virus (HTNV). Red blood cells (RBCs) are the major components of peripheral blood. However, pathological changes in RBCs and the underlying mechanisms during HTNV infection remain largely unclear. Therefore, this study sought to explore changes in RBCs in the peripheral blood of HFRS patients. We isolated PBMCs from HFRS patients and performed single-cell RNA sequencing. The results showed that clusters of RBCs in the peripheral blood of HFRS could be classified as nucleated red blood cells (NRBC) based on their cellular components, gene expression profiles and cell surface markers. In addition, it was shown that the higher the count of NRBC in peripheral blood, the more severe the disease status was. Moreover, hematological indices related to RBCs were analyzed and the results showed that impairment in the folate pathway might be the possible reason behind the presence of NRBCs. This study, for the first time showed that the presence of NRBCs in the peripheral blood of HFRS patients was associated with disease severity. This was also the first study to show that infection with the HTNV virus hindered the maturation of RBCs. Therefore, this work provides further insights on the role of and pathological changes in RBCs during HTNV infection.
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  • 文章类型: Journal Article
    Human infection of orthohantavirus can cause potentially fatal diseases, such as hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus (HTNV) in Eurasia. Exosomes are new carriers for information exchange between cells. Cumulative findings suggest that exosomes released from parental infected cells can block or promote viral infection in recipient cells, but the role of exosomes in hantavirus infection is poorly understood. In our study, we identified the exosomes derived from HTNV-infected human vascular endothelial cells (HUVECs) (Exo-HV) and found the antiviral properties of Exo-HV in the uninfected recipient cells. High-throughput sequencing revealed the distinctly expressed miRNAs transcriptomes in Exo-HV. MiR-145-5p, one of the abundant miRNAs packaged into Exo-HV, was found to be able to transferred to recipient cells and functioned by directly targeting M RNA of HTNV 76-118 and inducing type I interferon (IFN-I) response, thus, blocking the viral replication. Concluding, this study indicated that exosomes released by HTNV-infected HUVECs were able to transfer active molecules, miR-145-5p as a proving sample, to mediate novel anti-HTNV activity in the neighboring uninfected cells, which will help us to explore new strategies for the treatment of infectious disease utilizing exosomes with miRNA.
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