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D-dimer drives immune dysregulation in COVID-19 via chemokine modulation and inflammatory signaling d -二聚体通过趋化因子调节和炎症信号传导驱动COVID-19免疫失调。
IF 2.7 4区 医学 Q3 VIROLOGY Pub Date : 2025-10-11 DOI: 10.1016/j.virusres.2025.199641
Jingwei Hu , Min Liu , Binbin Qin , Bin Shen , Yingjun Huang , Jiayan Zhu , Qi Zheng , Xingdong Zheng , Jingyi Cai , Ying Xie , Yajun Song

Background

d-dimer, a fibrin degradation product and established marker of thrombosis, has been strongly associated with disease severity and poor prognosis in COVID-19. However, its role in immune modulation remains underexplored.

Methods

In this study, we enrolled 356 participants from Shanghai, including patients with mild and severe COVID-19 and SARS-CoV-2-negative controls. Clinical data were collected to assess correlations between d-dimer and immune-related markers. Public transcriptomic datasets, single-cell RNA sequencing (scRNA-seq), and in vitro stimulation of THP-1 cells with clinically relevant d-dimer concentrations were used to investigate d-dimer–associated immune responses.

Results

d-dimer levels were significantly elevated in severe COVID-19 patients and positively correlated with IL-6 and troponin I, while negatively associated with glomerular filtration rate. Integrated transcriptomic and protein interaction analyses identified IL-6 as a central hub in immune-related gene networks. scRNA-seq revealed tissue- and cell-specific IL-6 expression, predominantly in monocytes and T cells. In vitro d-dimer stimulation did not induce IL-6 expression in THP-1 cells but upregulated chemokines (e.g., CXCL5, CXCL6), and enriched key inflammatory pathways, including IL-17 and PI3K-Akt signaling.

Conclusion

These findings suggest that d-dimer may modulate the immune microenvironment by influencing chemokine-mediated cell recruitment, contributing to immune dysregulation in severe COVID-19. d-dimer functions not only as a clinical biomarker but also as a potential driver of thromboinflammatory responses.
背景:d -二聚体是一种纤维蛋白降解产物和血栓形成标志物,与COVID-19患者的疾病严重程度和不良预后密切相关。然而,其在免疫调节中的作用仍未得到充分研究。方法:在本研究中,我们从上海招募了356名参与者,包括轻、重度COVID-19患者和sars - cov -2阴性对照。收集临床数据以评估d -二聚体与免疫相关标志物之间的相关性。使用公共转录组数据集、单细胞RNA测序(scRNA-seq)和体外刺激具有临床相关d -二聚体浓度的THP-1细胞来研究d -二聚体相关的免疫反应。结果:d -二聚体水平在COVID-19重症患者中显著升高,与IL-6、肌钙蛋白I呈正相关,与肾小球滤过率负相关。综合转录组学和蛋白质相互作用分析确定IL-6是免疫相关基因网络的中心枢纽。scRNA-seq显示组织和细胞特异性IL-6表达,主要在单核细胞和T细胞中。体外d -二聚体刺激没有诱导THP-1细胞中IL-6的表达,但上调了趋化因子(如CXCL5、CXCL6),并丰富了关键的炎症通路,包括IL-17和PI3K-Akt信号。结论:d -二聚体可能通过影响趋化因子介导的细胞募集来调节免疫微环境,从而导致重症COVID-19患者的免疫失调。d -二聚体不仅作为临床生物标志物,而且作为血栓炎症反应的潜在驱动因素。
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引用次数: 0
Comparative small RNA profiles of beet mosaic virus (BtMV), beet mild yellowing virus (BMYV) and beet yellows virus (BYV) infected Nicotiana benthamiana and Beta vulgaris 甜菜花叶病毒(BtMV)、甜菜轻度黄化病毒(BMYV)和甜菜黄化病毒(BYV)侵染本烟和甜菜的小RNA谱比较。
IF 2.7 4区 医学 Q3 VIROLOGY Pub Date : 2025-10-10 DOI: 10.1016/j.virusres.2025.199640
Dennis Rahenbrock, Mark Varrelmann
Plants are constantly challenged by viral pathogens that can limit growth and reduce yield. A key component of the plant innate immunity is RNA silencing, in which viral double-stranded RNA (dsRNA) intermediates are recognised and processed into virus-derived small interfering RNAs (vsiRNAs). These vsiRNAs direct the degradation of viral genomes, thereby restricting infection. Sugar beet (Beta vulgaris subsp. vulgaris) is a crop of major economic importance, where the virus yellows (VY) complex represents a serious threat to production. Here, we profiled and compared vsiRNAs generated during infection of the natural host plant B. vulgaris and the experimental host plant Nicotiana benthamiana with three taxonomically distinct viruses: beet yellows virus (BYV, Closterovirus), beet mild yellowing virus (BMYV, Polerovirus), and beet mosaic virus (BtMV, Potyvirus). High-throughput sequencing of small RNAs revealed characteristic size distributions and strand biases that differed among viruses and host species. Comparative analysis highlighted no host plant-specific pattern of vsiRNA accumulation. This comparative approach provides a detailed view of vsiRNA processing and offers novel insights that are not apparent from coverage profiles alone. Distinct vsiRNA hotspots were detected for each viral genome, and these hotspots did not differ between host plants, pinpointing potential target regions for RNA interference-based control approaches. The identification of such regions provides a basis for the design of synthetic dsRNAs that can be applied exogenously as protective sprays, an emerging, non-transgenic strategy to mitigate VY infections, while advancing understanding of vsiRNA biogenesis in sugar beet and N. benthamiana in general.
植物不断受到病毒病原体的挑战,这些病原体可以限制生长并降低产量。植物先天免疫的一个关键组成部分是RNA沉默,其中病毒双链RNA (dsRNA)中间体被识别并加工成病毒衍生的小干扰RNA (vsirna)。这些vsirna指导病毒基因组的降解,从而限制感染。甜菜(Beta vulgaris subsp)是一种具有重要经济意义的作物,其中病毒黄(VY)复合体对生产构成严重威胁。在这里,我们分析和比较了天然寄主植物B. vulgaris和实验寄主植物Nicotiana benthamiana感染三种不同分类的病毒时产生的vsirna:甜菜黄病毒(BYV, clostervirus),甜菜轻度黄病毒(BMYV, Polerovirus)和甜菜花叶病毒(BtMV, Potyvirus)。小rna的高通量测序揭示了病毒和宿主物种之间不同的特征大小分布和链偏差。比较分析强调没有宿主植物特异性的vsiRNA积累模式。这种比较方法提供了vsiRNA加工的详细视图,并提供了仅从覆盖概况中不明显的新见解。在每个病毒基因组中检测到不同的vsiRNA热点,并且这些热点在宿主植物之间没有差异,这为基于RNA干扰的控制方法确定了潜在的靶点区域。这些区域的鉴定为设计合成的dsRNAs提供了基础,这些dsRNAs可以作为外源的保护性喷剂应用,这是一种新兴的非转基因策略,可以减轻VY感染,同时也促进了对甜菜和benthamiana中vsiRNA生物发生的理解。
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引用次数: 0
Isolation, genomic analysis and biocontrol potential of bacteriophage SHY-Vp8 and its endolysin against Vibrio parahaemolyticus in shrimp aquaculture 对虾养殖中抗副溶血性弧菌噬菌体SHY-Vp8及其内溶素的分离、基因组分析及生物防治潜力
IF 2.7 4区 医学 Q3 VIROLOGY Pub Date : 2025-10-09 DOI: 10.1016/j.virusres.2025.199638
Yijun Liu , Ge Jiang , Jie Cheng , Xiaotong Wang , Xianping Fan , Hailong Wu , Hui Shen
Vibrio parahaemolyticus causes mass mortality in global penaeid shrimp aquaculture worldwide, with lethality exceeding 90 %, threatening global food security and economic sustainability. As alternatives to antibiotics, bacteriophages and their lytic enzymes offer target specificity, minimal resistance development, and high bactericidal efficiency. In this study, ten phages were isolated from Litopenaeus vannamei aquaculture ponds and adjacent estuarine areas using Vp499 as the host, which were isolated by our lab. Among these, phage SHY-Vp8 exhibited the highest titer against the host Vp499.Its optimal multiplicity of infection (MOI) was determined to be 1. Notably, SHY-Vp8 demonstrated a superior lytic capacity, with a high burst size (96 PFU/cell) and a short latent period (30 min), representing an 18–41 % improvement in lytic efficiency over previously reported Vibrio phages. Furthermore, it exhibited exceptional environmental resilience, tolerating temperatures up to 60 °C and a broad pH range (3–12), surpassing the stability thresholds of most known vibriophages. Whole-genome sequencing indicated a double-stranded DNA genome of 58,525 bp with 46.38 % GC content. Bioinformatic annotation identified 85 predicted genes, of which 31 encoded functionally characterized proteins. No tRNA or virulence genes were detected, demonstrating potential for therapeutic applications in aquaculture. Transmission electron microscopy confirmed an icosahedral capsid and a long non-contractile tail, classifying SHY-Vp8 within the Siphoviridae family. Notably, the gp59 gene was predicted to encode an endolysin. The gene was amplified cloned and expressed. The lytic activity of Lys59 exhibited a concentration-dependent increase, with peak activity observed at 50 μg/mL. Lys59 alone was capable of lysing Vp499 without the aid of EDTA; however, pretreatment with EDTA significantly enhanced its lytic efficiency. Results indicate that both SHY-Vp8 and Lys59 exhibit promising potential for controlling V. parahaemolyticus infections in L. vannamei, offering a novel and sustainable strategy for disease management in aquaculture—particularly in pond water treatment and seafood safety enhancement. These excellent in vitro activities and characteristics provide a solid foundation for further development of in vivo infection models and eco-friendly biocontrol agents.
副溶血性弧菌在全球对虾养殖中造成大量死亡,致死率超过90%,威胁着全球粮食安全和经济可持续性。作为抗生素的替代品,噬菌体及其裂解酶具有靶向特异性、最小耐药性和高杀菌效率。本研究以Vp499为宿主,从凡纳滨对虾养殖池塘及邻近河口区分离得到10株噬菌体。其中,噬菌体hy - vp8对宿主Vp499的效价最高。确定其最优感染多重数(MOI)为1。值得注意的是,sh - vp8表现出优异的裂解能力,具有高爆发大小(96 PFU/细胞)和短潜伏期(30分钟),比先前报道的噬菌体弧菌的裂解效率提高了18-41%。此外,它还表现出了卓越的环境适应性,可耐受高达60°C的温度和广泛的pH范围(3-12),超过了大多数已知的噬菌体的稳定性阈值。全基因组测序结果显示,双链DNA基因组长度为58,525 bp, GC含量为46.38%。生物信息学注释鉴定出85个预测基因,其中31个编码功能特征蛋白。未检测到tRNA或毒力基因,表明其在水产养殖中的治疗应用潜力。透射电镜证实了一个二十面体衣壳和一个长而不可收缩的尾巴,将hy - vp8分类为Siphoviridae家族。值得注意的是,预测gp59基因编码一种内溶素。对该基因进行扩增、克隆和表达。Lys59的酶解活性呈浓度依赖性增加,在50 μg/mL时酶解活性最高。单独Lys59在没有EDTA的情况下也能裂解Vp499;EDTA预处理可显著提高其裂解效率。结果表明,SHY-Vp8和Lys59在控制凡纳梅副溶血性弧菌感染方面表现出良好的潜力,为水产养殖的疾病管理提供了一种新的可持续的策略,特别是在池塘水处理和提高海产品安全方面。这些良好的体外活性和特性为进一步开发体内感染模型和生态友好型生物防治剂提供了坚实的基础。
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引用次数: 0
Phase I clinical trial of a recombinant oncolytic virus injection combined with PD-1 antibody-based gene therapy for recurrent head and neck cancer in China: An open-label study 重组溶瘤病毒注射联合PD-1抗体基因治疗复发性头颈癌的I期临床试验:一项开放标签研究
IF 2.7 4区 医学 Q3 VIROLOGY Pub Date : 2025-10-08 DOI: 10.1016/j.virusres.2025.199639
Siyu Zhu , Qi Zhong , Yang Zhang , Lizhen Hou , Hongzhi Ma , Ling Feng , Xixi Shen , Jiaming Chen , Yurong He , Jingwen Lyu , Tiantian Wang , Rui Zhao , Jingfeng Li , Jugao Fang , Shizhi He
This study aims to evaluate the safety and preliminary efficacy of VT1093, an oncolytic recombinant herpes simplex virus type 1 (HSV-1) engineered to express a PD-1 monoclonal antibody, for the treatment of recurrent head and neck cancer. This open-label, single-arm, dose-escalation Phase I clinical trial was an exploratory dose-escalation study, in which the dose is progressively increased in enrolled patients until either the maximum tolerated dose (MTD) or dose-limiting toxicity (DLT) is identified. Seven patients with recurrent head and neck cancer were recruited at Beijing Tongren Hospital. Patients received either a single or multiple intratumoral injections of VT1093. For the single-dose group, patients were monitored for 28 days after treatment. For the multiple-dose group, three treatments were administered biweekly, with a 28-day follow-up after the final injection. Treatment efficacy and adverse events were monitored and recorded throughout the study. Of the seven patients enrolled, five were eligible for efficacy evaluation. Two patients did not return for follow-up evaluation after treatment and were classified as treatment ineffective. Four patients achieved stable disease (SD), while one had progressive disease (PD), resulting in a disease control rate (DCR) of 57.1 % (4/7). The most common treatment-related adverse events were mild to moderate fever and fatigue (Grade 1–2), with no Grade 3 or higher events. A promising immune profile was found in response to the oncolytic virus injection combined with PD-1 antibody. The treatment was generally well tolerated, and no DLTs were observed. VT1093 shows promising efficacy in controlling disease progression in recurrent head and neck cancer, with a favorable safety profile and low toxicity. These results support further clinical development of VT1093 as a novel therapeutic approach for this patient population.
本研究旨在评价溶瘤性重组1型单纯疱疹病毒(HSV-1)表达PD-1单克隆抗体VT1093治疗复发性头颈部癌的安全性和初步疗效。这项开放标签、单臂、剂量递增的I期临床试验是一项探索性剂量递增研究,在入组患者中,剂量逐步增加,直到确定最大耐受剂量(MTD)或剂量限制性毒性(DLT)。在北京同仁医院招募了7例复发性头颈癌患者。患者接受单次或多次肿瘤内注射VT1093。对于单剂量组,患者在治疗后监测28天。对于多剂量组,三次治疗每两周进行一次,最后一次注射后随访28天。在整个研究过程中监测和记录治疗疗效和不良事件。在入选的7名患者中,有5名符合疗效评估的条件。2例患者治疗后未返回随访评价,归类为治疗无效。4例病情稳定(SD), 1例病情进展(PD),疾病控制率(DCR)为57.1%(4/7)。最常见的治疗相关不良事件是轻度至中度发烧和疲劳(1-2级),没有3级或更高级别的不良事件。溶瘤病毒与PD-1抗体联合注射后,出现了良好的免疫应答。治疗总体耐受良好,未观察到dlt。VT1093在控制复发性头颈癌疾病进展方面显示出良好的疗效,具有良好的安全性和低毒性。这些结果支持了VT1093作为一种新型治疗方法的进一步临床开发。
{"title":"Phase I clinical trial of a recombinant oncolytic virus injection combined with PD-1 antibody-based gene therapy for recurrent head and neck cancer in China: An open-label study","authors":"Siyu Zhu ,&nbsp;Qi Zhong ,&nbsp;Yang Zhang ,&nbsp;Lizhen Hou ,&nbsp;Hongzhi Ma ,&nbsp;Ling Feng ,&nbsp;Xixi Shen ,&nbsp;Jiaming Chen ,&nbsp;Yurong He ,&nbsp;Jingwen Lyu ,&nbsp;Tiantian Wang ,&nbsp;Rui Zhao ,&nbsp;Jingfeng Li ,&nbsp;Jugao Fang ,&nbsp;Shizhi He","doi":"10.1016/j.virusres.2025.199639","DOIUrl":"10.1016/j.virusres.2025.199639","url":null,"abstract":"<div><div>This study aims to evaluate the safety and preliminary efficacy of VT1093, an oncolytic recombinant herpes simplex virus type 1 (HSV-1) engineered to express a PD-1 monoclonal antibody, for the treatment of recurrent head and neck cancer. This open-label, single-arm, dose-escalation Phase I clinical trial was an exploratory dose-escalation study, in which the dose is progressively increased in enrolled patients until either the maximum tolerated dose (MTD) or dose-limiting toxicity (DLT) is identified. Seven patients with recurrent head and neck cancer were recruited at Beijing Tongren Hospital. Patients received either a single or multiple intratumoral injections of VT1093. For the single-dose group, patients were monitored for 28 days after treatment. For the multiple-dose group, three treatments were administered biweekly, with a 28-day follow-up after the final injection. Treatment efficacy and adverse events were monitored and recorded throughout the study. Of the seven patients enrolled, five were eligible for efficacy evaluation. Two patients did not return for follow-up evaluation after treatment and were classified as treatment ineffective. Four patients achieved stable disease (SD), while one had progressive disease (PD), resulting in a disease control rate (DCR) of 57.1 % (4/7). The most common treatment-related adverse events were mild to moderate fever and fatigue (Grade 1–2), with no Grade 3 or higher events. A promising immune profile was found in response to the oncolytic virus injection combined with PD-1 antibody. The treatment was generally well tolerated, and no DLTs were observed. VT1093 shows promising efficacy in controlling disease progression in recurrent head and neck cancer, with a favorable safety profile and low toxicity. These results support further clinical development of VT1093 as a novel therapeutic approach for this patient population.</div></div>","PeriodicalId":23483,"journal":{"name":"Virus research","volume":"361 ","pages":"Article 199639"},"PeriodicalIF":2.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Molecular and structural insights into dengue virus non-structural proteins from pakistani clinical isolates for the identification of novel antiviral targets 从巴基斯坦临床分离的登革病毒非结构蛋白中鉴定新的抗病毒靶点的分子和结构见解
IF 2.7 4区 医学 Q3 VIROLOGY Pub Date : 2025-10-03 DOI: 10.1016/j.virusres.2025.199637
Liaqat Ali , Nida Kanwal , Iffat Saleem , Haidar Ali , Deeba Amraiz , Madiha Akram , Imran Shahid , Jing Yang
Dengue virus (DENV) remains a global health threat, with Pakistan experiencing recurrent outbreaks, yet non-structural genes (NS1, NS2A, NS5) critical for viral replication and pathogenesis remain understudied in local strains. In this study, 150 NS1-positive serum samples (2022–2024) were analyzed via nested PCR, Sanger sequencing, and phylogenetic tools (MEGA11), revealing DENV-2 as the dominant serotype (85 % of samples), with NS5 showing 97 % homology to Indian/Swat strains, while NS1 and NS2A exhibited sequence variation in functional domains. In silico modeling and docking studies identified RK-0404,678 as a strong binder to NS5 (−6.4 kcal/mol) and Galidesivir to NS5 (−7.2 kcal/mol), suggesting their potential as antiviral candidates. These findings highlight DENV-2 dominance in Pakistan and identify conserved regions in NS5 as promising drug targets, though further experimental validation is warranted.
登革热病毒(DENV)仍然是全球健康威胁,巴基斯坦正在经历反复暴发,但对病毒复制和发病机制至关重要的非结构基因(NS1、NS2A、NS5)在当地菌株中的研究仍不足。本研究通过巢式PCR、Sanger测序和系统发育工具(MEGA11)分析了150份NS1阳性血清样本(2022-2024),发现DENV-2为优势血清型(85%的样本),其中NS5与印度/Swat菌株具有97%的同源性,而NS1和NS2A在功能域上存在序列差异。计算机建模和对接研究发现,RK-0404678与NS5 (-6.4 kcal/mol)和Galidesivir与NS5 (-7.2 kcal/mol)具有很强的结合,表明它们具有抗病毒候选药物的潜力。这些发现强调了DENV-2在巴基斯坦的优势地位,并确定了NS5的保守区域是有希望的药物靶点,尽管需要进一步的实验验证。
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引用次数: 0
Effect of interleukin-17A on anti-ANT antibodies as well as cytokines in viral myocarditis mice 白细胞介素- 17a对病毒性心肌炎小鼠抗ant抗体及细胞因子的影响。
IF 2.7 4区 医学 Q3 VIROLOGY Pub Date : 2025-09-27 DOI: 10.1016/j.virusres.2025.199635
Weiwei Li , Wei Jiao , Fang Li , Jie Hao
<div><h3>Objective</h3><div>To observe the effect of interleukin-17A (IL-17A) on serum anti-mitochondrial endosomal ADP/ATP carrier autoantibody (anti-ANT antibody) levels and cytokines in viral myocarditis (VMC) mice.</div></div><div><h3>Methods</h3><div>Male wild-type (WT) and IL-17A knockout (IL-17A<sup>−/−</sup>) BALB/c mice were intraperitoneally injected with coxsackievirus B3 (CVB3) to establish a VMC model (VMC-WT and VMC-IL-17A<sup>−/−</sup>), while WT BALB/c mice were injected with PBS intraperitoneally to establish a normal control group (WT group). After 14 days, myocardial tissues were taken to calculate heart mass, and paraffin sections were prepared and stained with HE staining to observe the pathological changes and calculate the pathological score of myocardial tissues. Flow cytometry was used to detect the level of CD4<sup>+</sup> T lymphocytes in peripheral blood, ELISA was used to determine the level of anti-ANT antibody, IL-17 and IL-23 in serum, and Western blotting was used to detect the expression level of IL-17 and IL-23 proteins in myocardial tissue.</div></div><div><h3>Results</h3><div>VMC mice were successfully constructed. Mice in the WT group showed no abnormal activity; Mice in the VMC-WT group gradually showed behaviors such as huddling, shrugging, trembling, and poor response from the third day of injection; Mice in the VMC-IL-17A<sup>−/−</sup> group showed the above symptoms to a lesser extent. In the VMC-WT group, the HM and pathological score were 5.62 ± 0.27 g/kg and 3.12 ± 0.45 score. The HM and pathologic score in the VMC-IL-17A<sup>−/−</sup> group were lower than those in the VMC-WT group. The pathological examination of WT mice showed no inflammatory cell infiltration and patchy necrosis. The rats in VMC-WT group showed extensive inflammatory cell infiltration and large sheet necrosis of cardiomyocytes under microscope. Compared with the VMC-WT group, the VMC-IL-17A<sup>−/−</sup> group showed focal myocardial necrosis and significantly reduced inflammatory cell infiltration 14 days after CVB3 infection. At the same time, the percentage of CD4<sup>+</sup>T was remarkably lower in the VMC-WT mice compared with the WT mice. The percentage of CD4<sup>+</sup>T was higher in the VMC-IL-17A<sup>−/−</sup> group (27.54 ± 3.62) than in the VMC-WT group (16.97 ± 2.18). In addition, anti-ANT antibody (1.48 ± 0.31 μg/L), IL-17 (33.47 ± 4.26 pg/mL) and IL-23 (32.42 ± 4.31 pg/mL) levels were significantly lower in serum of VMC-IL-17A<sup>−/−</sup> mice than in the VMC-WT mice. At the protein level, the expression of IL-17 and IL-23 showed consistent results.</div></div><div><h3>Conclusion</h3><div>Serum anti-ANT antibody, IL-17, and IL-23 levels were significantly elevated in VMC mice. Although the ELISA results suggest IL-17A is involved in the production of anti-ANT antibody in VMC mice, the possibility of cross-reactivity cannot be completely ruled out; therefore, the results should be interpreted with caution. The kn
目的:观察白细胞介素- 17a (IL-17A)对病毒性心肌炎(VMC)小鼠血清抗线粒体内体ADP/ATP载体自身抗体(anti-ANT抗体)水平及细胞因子的影响。方法:雄性野生型(WT)和IL-17A敲除型(IL-17A-/-) BALB/c小鼠腹腔注射柯萨奇病毒B3 (CVB3)建立VMC模型(VMC-WT和VMC-IL-17A-/-), WT型BALB/c小鼠腹腔注射PBS建立正常对照组(WT组)。14d后取心肌组织计算心脏质量,制作石蜡切片,HE染色,观察心肌组织病理变化,计算心肌组织病理评分。采用流式细胞术检测外周血CD4+ T淋巴细胞水平,ELISA检测血清中抗ant抗体、IL-17、IL-23水平,Western blotting检测心肌组织中IL-17、IL-23蛋白表达水平。结果:成功构建VMC小鼠。WT组小鼠无异常活动;VMC-WT组小鼠从注射第3天开始逐渐出现蜷缩、耸肩、颤抖等行为,反应较差;VMC-IL-17A-/-组小鼠出现上述症状的程度较轻。VMC-WT组HM、病理评分分别为5.62±0.27 g/kg、3.12±0.45分。VMC-IL-17A-/-组HM和病理评分均低于VMC-WT组。WT小鼠病理检查未见炎症细胞浸润和斑片状坏死。VMC-WT组大鼠显微镜下可见广泛的炎症细胞浸润和心肌细胞大面积坏死。与VMC-WT组比较,CVB3感染14天后,VMC-IL-17A-/-组出现局灶性心肌坏死,炎症细胞浸润明显减少。与此同时,VMC-WT小鼠的CD4+T百分比明显低于WT小鼠。VMC-IL-17A-/-组CD4+T百分比(27.54±3.62)高于VMC-WT组(16.97±2.18)。此外,VMC-IL-17A-/-小鼠血清中抗ant抗体(1.48±0.31 μg/L)、IL-17(33.47±4.26 pg/mL)和IL-23(32.42±4.31 pg/mL)水平显著低于VMC-WT小鼠。在蛋白水平上,IL-17和IL-23的表达结果一致。结论:VMC小鼠血清抗ant抗体、IL-17、IL-23水平显著升高。虽然ELISA结果提示IL-17A参与了VMC小鼠抗ant抗体的产生,但不能完全排除其交叉反应的可能性;因此,研究结果应谨慎解读。IL-17A基因敲低与VMC小鼠心肌炎症抑制、外周血CD4+ T淋巴细胞升高、心肌损伤减轻有关。
{"title":"Effect of interleukin-17A on anti-ANT antibodies as well as cytokines in viral myocarditis mice","authors":"Weiwei Li ,&nbsp;Wei Jiao ,&nbsp;Fang Li ,&nbsp;Jie Hao","doi":"10.1016/j.virusres.2025.199635","DOIUrl":"10.1016/j.virusres.2025.199635","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;div&gt;To observe the effect of interleukin-17A (IL-17A) on serum anti-mitochondrial endosomal ADP/ATP carrier autoantibody (anti-ANT antibody) levels and cytokines in viral myocarditis (VMC) mice.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Male wild-type (WT) and IL-17A knockout (IL-17A&lt;sup&gt;−/−&lt;/sup&gt;) BALB/c mice were intraperitoneally injected with coxsackievirus B3 (CVB3) to establish a VMC model (VMC-WT and VMC-IL-17A&lt;sup&gt;−/−&lt;/sup&gt;), while WT BALB/c mice were injected with PBS intraperitoneally to establish a normal control group (WT group). After 14 days, myocardial tissues were taken to calculate heart mass, and paraffin sections were prepared and stained with HE staining to observe the pathological changes and calculate the pathological score of myocardial tissues. Flow cytometry was used to detect the level of CD4&lt;sup&gt;+&lt;/sup&gt; T lymphocytes in peripheral blood, ELISA was used to determine the level of anti-ANT antibody, IL-17 and IL-23 in serum, and Western blotting was used to detect the expression level of IL-17 and IL-23 proteins in myocardial tissue.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;VMC mice were successfully constructed. Mice in the WT group showed no abnormal activity; Mice in the VMC-WT group gradually showed behaviors such as huddling, shrugging, trembling, and poor response from the third day of injection; Mice in the VMC-IL-17A&lt;sup&gt;−/−&lt;/sup&gt; group showed the above symptoms to a lesser extent. In the VMC-WT group, the HM and pathological score were 5.62 ± 0.27 g/kg and 3.12 ± 0.45 score. The HM and pathologic score in the VMC-IL-17A&lt;sup&gt;−/−&lt;/sup&gt; group were lower than those in the VMC-WT group. The pathological examination of WT mice showed no inflammatory cell infiltration and patchy necrosis. The rats in VMC-WT group showed extensive inflammatory cell infiltration and large sheet necrosis of cardiomyocytes under microscope. Compared with the VMC-WT group, the VMC-IL-17A&lt;sup&gt;−/−&lt;/sup&gt; group showed focal myocardial necrosis and significantly reduced inflammatory cell infiltration 14 days after CVB3 infection. At the same time, the percentage of CD4&lt;sup&gt;+&lt;/sup&gt;T was remarkably lower in the VMC-WT mice compared with the WT mice. The percentage of CD4&lt;sup&gt;+&lt;/sup&gt;T was higher in the VMC-IL-17A&lt;sup&gt;−/−&lt;/sup&gt; group (27.54 ± 3.62) than in the VMC-WT group (16.97 ± 2.18). In addition, anti-ANT antibody (1.48 ± 0.31 μg/L), IL-17 (33.47 ± 4.26 pg/mL) and IL-23 (32.42 ± 4.31 pg/mL) levels were significantly lower in serum of VMC-IL-17A&lt;sup&gt;−/−&lt;/sup&gt; mice than in the VMC-WT mice. At the protein level, the expression of IL-17 and IL-23 showed consistent results.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Serum anti-ANT antibody, IL-17, and IL-23 levels were significantly elevated in VMC mice. Although the ELISA results suggest IL-17A is involved in the production of anti-ANT antibody in VMC mice, the possibility of cross-reactivity cannot be completely ruled out; therefore, the results should be interpreted with caution. The kn","PeriodicalId":23483,"journal":{"name":"Virus research","volume":"361 ","pages":"Article 199635"},"PeriodicalIF":2.7,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Impact of IL10 polymorphism in chronic progression of hepatitis B virus infection il - 10多态性在乙型肝炎病毒感染慢性进展中的影响
IF 2.7 4区 医学 Q3 VIROLOGY Pub Date : 2025-09-27 DOI: 10.1016/j.virusres.2025.199636
Yasmine Chelbi , Manel Hamdoun , Hamza Cherni , Hinda Triki , Melika Ben Ahmed , Olfa Bahri
Chronic infection with the hepatitis B virus (HBV) remains a major public health issue. Its progression depends on several factors, including immunogenetic factors. The aim of this study was to investigate the association between interleukin 10 gene (IL10) polymorphism and the progression of this infection. This retrospective case-control study involved 156 chronic HBV carriers (CHBV-C) and 174 healthy HBV-negative controls (HBsAg-). The analysis of IL10 promoter polymorphism was carried out using the TaqMan allele discrimination technique at two single nucleotide polymorphisms (SNPs), -592A>C (rs1800872) and -1082A>G (rs1800896), of the IL10 promoter. IL10 levels were measured using an in-house Enzyme-Linked Immunosorbent Assay (ELISA) for all patients chronically infected by HBV who had not yet received treatment. Chronic HBV infection (CBI) was present in 32% (n = 43) of cases, 37% (n = 51) had active chronic hepatitis (ACH), and 31% had complicated hepatitis. The analysis of allele polymorphism identified six genotypes: AA (14%), AC (43%), and CC (43%) for SNP-592A>C, and AA (41%), AG (45%) and GG (14%) for SNP-1082A>G. The only genotype that was substantially more common in CHBV-C patients was -1082/GG (OR=1.9; CI95%=[1,3.62]; p = 0.046). When compared to controls, the IL10 level was significantly higher in CBI patients (3.27 vs. 2.56 pg/ml;p = 0.002). Significantly higher IL10 levels were also linked to the genotypes -1082 GG (6.02 pg/ml;p = 0.04) and -592CC (3.73 pg/ml;p = 0.039). With the -592 AA genotype, this level was noticeably lower (1.35 pg/ml;p = 0.014). These findings support the hypothesis that the development of chronicity in HBV infection is linked to elevated IL10 levels and the -1082 GG genotype in the gene's promoter.
慢性乙型肝炎病毒(HBV)感染仍然是一个主要的公共卫生问题。其进展取决于几个因素,包括免疫遗传因素。本研究的目的是探讨白细胞介素10基因(IL10)多态性与这种感染的进展之间的关系。这项回顾性病例对照研究涉及156名慢性HBV携带者(CHBV-C)和174名健康HBV阴性对照(HBsAg-)。利用TaqMan等位基因识别技术对IL10启动子的-592A>C (rs1800872)和-1082A>G (rs1800896)两个单核苷酸多态性(snp)进行多态性分析。使用内部酶联免疫吸附试验(ELISA)测量所有尚未接受治疗的慢性HBV感染患者的il - 10水平。32% (n=43)的病例存在慢性HBV感染(CBI), 37% (n=51)有活动性慢性肝炎(ACH), 31%有并发肝炎。等位基因多态性分析鉴定出6种基因型:SNP-592A>C为AA(14%)、AC(43%)和CC (43%), SNP-1082A>G为AA(41%)、AG(45%)和GG(14%)。唯一在CHBV-C患者中更常见的基因型是-1082/GG (OR=1.9; CI95%=[1,3.62]; p=0.046)。与对照组相比,CBI患者的IL10水平显著高于对照组(3.27 vs 2.56 pg/ml;p=0.002)。显著升高的IL10水平也与基因型-1082 GG (6.02 pg/ml, p=0.04)和-592CC (3.73 pg/ml, p=0.039)相关。对于-592 AA基因型,这一水平明显较低(1.35 pg/ml;p=0.014)。这些发现支持了一种假设,即HBV感染的慢性发展与IL10水平升高和该基因启动子的-1082 GG多态性有关。
{"title":"Impact of IL10 polymorphism in chronic progression of hepatitis B virus infection","authors":"Yasmine Chelbi ,&nbsp;Manel Hamdoun ,&nbsp;Hamza Cherni ,&nbsp;Hinda Triki ,&nbsp;Melika Ben Ahmed ,&nbsp;Olfa Bahri","doi":"10.1016/j.virusres.2025.199636","DOIUrl":"10.1016/j.virusres.2025.199636","url":null,"abstract":"<div><div>Chronic infection with the hepatitis B virus (HBV) remains a major public health issue. Its progression depends on several factors, including immunogenetic factors. The aim of this study was to investigate the association between interleukin 10 gene (<em>IL10</em>) polymorphism and the progression of this infection. This retrospective case-control study involved 156 chronic HBV carriers (CHBV-C) and 174 healthy HBV-negative controls (HBsAg-). The analysis of <em>IL10</em> promoter polymorphism was carried out using the TaqMan allele discrimination technique at two single nucleotide polymorphisms (SNPs), -592A&gt;<em>C</em> (rs1800872) and -1082A&gt;<em>G</em> (rs1800896), of the <em>IL10</em> promoter. IL10 levels were measured using an in-house Enzyme-Linked Immunosorbent Assay (ELISA) for all patients chronically infected by HBV who had not yet received treatment. Chronic HBV infection (CBI) was present in 32% (<em>n</em> = 43) of cases, 37% (<em>n</em> = 51) had active chronic hepatitis (ACH), and 31% had complicated hepatitis. The analysis of allele polymorphism identified six genotypes: AA (14%), AC (43%), and CC (43%) for SNP-592A&gt;<em>C</em>, and AA (41%), AG (45%) and GG (14%) for SNP-1082A&gt;<em>G</em>. The only genotype that was substantially more common in CHBV-C patients was -1082/GG (OR=1.9; CI95%=[1,3.62]; <em>p</em> = 0.046). When compared to controls, the IL10 level was significantly higher in CBI patients (3.27 vs. 2.56 pg/ml;<em>p</em> = 0.002). Significantly higher IL10 levels were also linked to the genotypes -1082 GG (6.02 pg/ml;<em>p</em> = 0.04) and -592CC (3.73 pg/ml;<em>p</em> = 0.039). With the -592 AA genotype, this level was noticeably lower (1.35 pg/ml;<em>p</em> = 0.014). These findings support the hypothesis that the development of chronicity in HBV infection is linked to elevated IL10 levels and the -1082 GG genotype in the gene's promoter.</div></div>","PeriodicalId":23483,"journal":{"name":"Virus research","volume":"361 ","pages":"Article 199636"},"PeriodicalIF":2.7,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Identification of H1N2 influenza viruses in turkeys after spillover from swine and in vitro characterization 猪流感病毒外溢后火鸡中H1N2流感病毒的鉴定及体外鉴定。
IF 2.7 4区 医学 Q3 VIROLOGY Pub Date : 2025-09-21 DOI: 10.1016/j.virusres.2025.199634
Chloé Chavoix , Pascale Massin , François-Xavier Briand , Katell Louboutin , Rachel Busson , Florent Souchaud , Gautier Richard , Claire Martenot , Aurélie Le Roux , Edouard Hirchaud , Yannick Blanchard , Sophie Le Bouquin-Leneveu , Axelle Scoizec , Céline Deblanc , Séverine Hervé , Audrey Schmitz , Eric Niqueux , Gaëlle Simon , Ronan Le Goffic , Béatrice Grasland
Influenza A viruses (IAVs) circulate among animals and humans and can cross species barriers to adapt to new hosts. In France, since 2020, a new genotype named H1avN2#E has predominated in pig farms. In parallel, this virus was detected in 19 breeding turkey flocks and in a human case, indicating interspecies transmission. The objectives of this study were (i) to analyze viral sequences detected in turkeys between April 2020 and January 2023 and compare them with swine sequences to identify potential markers of adaptation and (ii) to characterize three representative viruses in vitro and in ovo on MDCK, MLE15 and A549 cells, as well as on embryonated chicken eggs. Results suggest that following initial swine-to-turkey spillovers, the virus circulated between turkey farms. Phylogenetic analyses and host origin guided the selection of three viruses: a reference swine virus (A), a turkey strain closely related to swine viruses (B) and a virus apparently circulating in turkeys (C). Three molecular markers may contribute to turkey adaptation: the E233K, under positive selection pressure, or E236K mutations in the 220-loop of the receptor-binding site of HA protein and two NA substitutions, T401N in antigenic site 2d and S416N. Replication kinetics showed that at low MOI (0.001), virus C produced more infectious particles on MDCK and A549 cells, whereas at high MOI (0.1), virus B produced more. In ovo, infectious particles were generated for viruses A and B but not efficiently for virus C, in contrast to mammalian cells where production was higher.
甲型流感病毒(iav)在动物和人类之间传播,并能跨越物种障碍以适应新的宿主。在法国,自2020年以来,一种名为H1avN2#E的新基因型在养猪场占主导地位。同时,在19个养殖火鸡群和1例人间病例中发现了该病毒,表明存在种间传播。本研究的目的是:(i)分析2020年4月至2023年1月期间在火鸡中检测到的病毒序列,并将其与猪的序列进行比较,以确定潜在的适应标记;(ii)在MDCK、MLE15和A549细胞以及胚胎鸡蛋上,对三种体外和蛋内的代表性病毒进行表征。结果表明,在最初的猪对火鸡的溢出之后,病毒在火鸡养殖场之间传播。系统发育分析和宿主来源指导了三种病毒的选择:参考猪病毒(a),与猪病毒密切相关的火鸡毒株(B)和明显在火鸡中传播的病毒(C)。三种分子标记可能有助于火鸡的适应:在正选择压力下的E233K,或HA蛋白受体结合位点220环的E236K突变和两个NA替换,抗原位点2d和S416N的T401N。复制动力学表明,在低MOI(0.001)时,病毒C在MDCK和A549细胞上产生更多的感染性颗粒,而在高MOI(0.1)时,病毒B产生更多的感染性颗粒。在卵细胞中,病毒A和病毒B可以产生感染性颗粒,但病毒C不能有效地产生感染性颗粒,而哺乳动物细胞的感染性颗粒的产生率更高。
{"title":"Identification of H1N2 influenza viruses in turkeys after spillover from swine and in vitro characterization","authors":"Chloé Chavoix ,&nbsp;Pascale Massin ,&nbsp;François-Xavier Briand ,&nbsp;Katell Louboutin ,&nbsp;Rachel Busson ,&nbsp;Florent Souchaud ,&nbsp;Gautier Richard ,&nbsp;Claire Martenot ,&nbsp;Aurélie Le Roux ,&nbsp;Edouard Hirchaud ,&nbsp;Yannick Blanchard ,&nbsp;Sophie Le Bouquin-Leneveu ,&nbsp;Axelle Scoizec ,&nbsp;Céline Deblanc ,&nbsp;Séverine Hervé ,&nbsp;Audrey Schmitz ,&nbsp;Eric Niqueux ,&nbsp;Gaëlle Simon ,&nbsp;Ronan Le Goffic ,&nbsp;Béatrice Grasland","doi":"10.1016/j.virusres.2025.199634","DOIUrl":"10.1016/j.virusres.2025.199634","url":null,"abstract":"<div><div>Influenza A viruses (IAVs) circulate among animals and humans and can cross species barriers to adapt to new hosts. In France, since 2020, a new genotype named H1<sub>av</sub>N2#E has predominated in pig farms. In parallel, this virus was detected in 19 breeding turkey flocks and in a human case, indicating interspecies transmission. The objectives of this study were (i) to analyze viral sequences detected in turkeys between April 2020 and January 2023 and compare them with swine sequences to identify potential markers of adaptation and (ii) to characterize three representative viruses <em>in vitro</em> and <em>in ovo</em> on MDCK, MLE15 and A549 cells, as well as on embryonated chicken eggs. Results suggest that following initial swine-to-turkey spillovers, the virus circulated between turkey farms. Phylogenetic analyses and host origin guided the selection of three viruses: a reference swine virus (A), a turkey strain closely related to swine viruses (B) and a virus apparently circulating in turkeys (C). Three molecular markers may contribute to turkey adaptation: the E233K, under positive selection pressure, or E236K mutations in the 220-loop of the receptor-binding site of HA protein and two NA substitutions, T401N in antigenic site 2d and S416N. Replication kinetics showed that at low MOI (0.001), virus C produced more infectious particles on MDCK and A549 cells, whereas at high MOI (0.1), virus B produced more. <em>In ovo</em>, infectious particles were generated for viruses A and B but not efficiently for virus C, in contrast to mammalian cells where production was higher.</div></div>","PeriodicalId":23483,"journal":{"name":"Virus research","volume":"361 ","pages":"Article 199634"},"PeriodicalIF":2.7,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145132012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Association between COVID-19 vaccination and progression to severe outcomes in hospitalized COVID-19 patients in Hungary during the pre-Omicron era of the COVID-19 pandemic 在匈牙利COVID-19大流行前欧米克隆时代,COVID-19疫苗接种与住院COVID-19患者进展为严重结局之间的关系
IF 2.7 4区 医学 Q3 VIROLOGY Pub Date : 2025-09-18 DOI: 10.1016/j.virusres.2025.199633
Zoltán Vokó , Gergő Túri , Beatrix Oroszi , Éva Belicza , Tamás Kováts , Veronika Müller , János Réthelyi , Attila Szijártó , Tamás Masszi , István Takács , János Gál , Zsolt Göböl , Attila Szabó , Csaba Varga , Dávid Becker , Béla Merkely
COVID-19 vaccines reduce hospitalization risk, but data on severe outcomes are limited. We analyzed the impact of COVID-19 vaccination on severe outcomes in hospitalized patients in Hungary during the pre-Omicron era, addressing a regional knowledge gap. This retrospective study included hospitalized patients with PCR-confirmed COVID-19 (March 2020 – December 2021) who were categorized as unvaccinated, primary immunized, or booster-vaccinated. Outcomes included oxygen therapy, ventilation types, ECMO, and death, with the most severe outcome as the primary outcome and individual outcomes as secondary measures. Polytomous logistic regression calculated relative risk ratios for the primary outcome and COVID-19 vaccination status, while logistic regression estimated odds ratios for individual outcomes. During the study, 7575 patients were hospitalized with PCR-confirmed COVID-19: 6420 (84.8 %) were unvaccinated, 1016 (13.4 %) received a primary vaccination series, and 139 (1.8 %) had received a booster dose. COVID-19 vaccination reduced the risk of both invasive ventilation and in-hospital death as the most severe outcome by 50 % within 12 months (relative risk ratio [RRR]: 0.52, 95 % CI: 0.30–0.89; 0.50, 95 % CI: 0.41–0.61). Booster doses within six months decreased the risk of in-hospital death to a similar extent (RRR 0.46, 95 % CI: 0.30–0.72). Primary and booster vaccination reduced the risk of progression to severe outcomes in hospitalized COVID-19 patients.
COVID-19疫苗可降低住院风险,但关于严重后果的数据有限。我们分析了COVID-19疫苗接种对匈牙利住院患者在欧米克隆时代之前的严重结局的影响,解决了区域知识差距。这项回顾性研究纳入了pcr确诊的2019冠状病毒病住院患者(2020年3月至2021年12月),他们被分类为未接种疫苗、初次接种疫苗或加强接种疫苗。结果包括氧疗、通气类型、ECMO和死亡,以最严重结果为主要结果,个体结果为次要指标。多元逻辑回归计算了主要结局和COVID-19疫苗接种状况的相对风险比,而逻辑回归估计了个体结局的优势比。在研究期间,因pcr确诊的COVID-19住院的7575例患者中,6420例(84.8%)未接种疫苗,1016例(13.4%)接种了一次疫苗系列,139例(1.8%)接种了加强剂量。COVID-19疫苗在12个月内将有创通气和院内死亡作为最严重结局的风险降低了50%(相对风险比[RRR]: 0.52, 95% CI: 0.30-0.89; 0.50, 95% CI: 0.41-0.61)。6个月内加强剂量降低住院死亡风险的程度相似(RRR 0.46, 95% CI: 0.30-0.72)。初次和加强疫苗接种降低了住院COVID-19患者进展为严重结局的风险。
{"title":"Association between COVID-19 vaccination and progression to severe outcomes in hospitalized COVID-19 patients in Hungary during the pre-Omicron era of the COVID-19 pandemic","authors":"Zoltán Vokó ,&nbsp;Gergő Túri ,&nbsp;Beatrix Oroszi ,&nbsp;Éva Belicza ,&nbsp;Tamás Kováts ,&nbsp;Veronika Müller ,&nbsp;János Réthelyi ,&nbsp;Attila Szijártó ,&nbsp;Tamás Masszi ,&nbsp;István Takács ,&nbsp;János Gál ,&nbsp;Zsolt Göböl ,&nbsp;Attila Szabó ,&nbsp;Csaba Varga ,&nbsp;Dávid Becker ,&nbsp;Béla Merkely","doi":"10.1016/j.virusres.2025.199633","DOIUrl":"10.1016/j.virusres.2025.199633","url":null,"abstract":"<div><div>COVID-19 vaccines reduce hospitalization risk, but data on severe outcomes are limited. We analyzed the impact of COVID-19 vaccination on severe outcomes in hospitalized patients in Hungary during the pre-Omicron era, addressing a regional knowledge gap. This retrospective study included hospitalized patients with PCR-confirmed COVID-19 (March 2020 – December 2021) who were categorized as unvaccinated, primary immunized, or booster-vaccinated. Outcomes included oxygen therapy, ventilation types, ECMO, and death, with the most severe outcome as the primary outcome and individual outcomes as secondary measures. Polytomous logistic regression calculated relative risk ratios for the primary outcome and COVID-19 vaccination status, while logistic regression estimated odds ratios for individual outcomes. During the study, 7575 patients were hospitalized with PCR-confirmed COVID-19: 6420 (84.8 %) were unvaccinated, 1016 (13.4 %) received a primary vaccination series, and 139 (1.8 %) had received a booster dose. COVID-19 vaccination reduced the risk of both invasive ventilation and in-hospital death as the most severe outcome by 50 % within 12 months (relative risk ratio [RRR]: 0.52, 95 % CI: 0.30–0.89; 0.50, 95 % CI: 0.41–0.61). Booster doses within six months decreased the risk of in-hospital death to a similar extent (RRR 0.46, 95 % CI: 0.30–0.72). Primary and booster vaccination reduced the risk of progression to severe outcomes in hospitalized COVID-19 patients.</div></div>","PeriodicalId":23483,"journal":{"name":"Virus research","volume":"361 ","pages":"Article 199633"},"PeriodicalIF":2.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Evaluation of Potential Inhibitors of Zika Virus Envelope Protein Through Molecular Docking and Molecular Dynamics Simulation 寨卡病毒包膜蛋白潜在抑制剂分子对接及动力学模拟分析
IF 2.7 4区 医学 Q3 VIROLOGY Pub Date : 2025-09-11 DOI: 10.1016/j.virusres.2025.199630
Jehad Zuhair Tayyeb , Maria Karolaynne da Silva , Aamal A. Al-Mutairi , Hanan M. Alharbi , Alaa A. Khojah , Imren Bayıl , Abdullah Yahya Abdullah Alzahrani , Zsolt Tóth , Jonas Ivan Nobre Oliveira , Magdi E.A. Zaki
Zika virus (ZIKV) infection remains a global health threat with no approved antivirals or vaccines to date, creating an urgent need for therapeutics targeting ZIKV. The viral envelope (E) protein is critical for host cell entry and represents a validated target for antiviral intervention. Here, we aimed to identify natural flavonoid compounds capable of inhibiting the ZIKV E protein using a dual-phase in silico screening strategy. First, we performed density functional theory (DFT) calculations to optimize the structures of nine candidate flavonoids and obtain quantum chemical descriptors (electronic properties); we also evaluated their drug-likeness and ADMET profiles. Second, we conducted molecular docking of these optimized flavonoids to the E protein, followed by hybrid quantum mechanics/molecular mechanics (QM/MM) refinement and 100 ns molecular dynamics (MD) simulations with principal component analysis (PCA) and MM-PBSA binding free energy calculations to assess binding interactions and complex stability. Docking identified quercetin, pinocembrin, and naringenin as the top binders, with binding energies of –8.3, –8.1, and –8.0 kcal/mol, respectively. These lead flavonoids also exhibited favorable pharmacokinetic properties, including high predicted gastrointestinal absorption, efficient clearance, and minimal toxicity risk (no carcinogenic or organ-specific alerts). Notably, pinocembrin’s complex demonstrated the greatest stability throughout a 100 ns MD simulation, maintaining a tightly bound conformation. In conclusion, quercetin, pinocembrin, and naringenin emerge as promising ZIKV E protein inhibitors with robust target engagement and favorable drug-like profiles. Their significant translational potential as antiviral candidates warrants further in vitro and in vivo studies to confirm efficacy and safety.
寨卡病毒(ZIKV)感染仍然是全球健康威胁,迄今为止没有批准的抗病毒药物或疫苗,因此迫切需要针对寨卡病毒的治疗方法。病毒包膜(E)蛋白对宿主细胞进入至关重要,是抗病毒干预的有效靶标。在这里,我们旨在利用双相硅筛选策略鉴定能够抑制ZIKV E蛋白的天然类黄酮化合物。首先,我们通过密度泛函理论(DFT)计算优化了9种候选类黄酮的结构,并获得了量子化学描述符(电子性质);我们还评估了他们的药物相似性和ADMET特征。其次,我们将优化后的黄酮类化合物与E蛋白进行分子对接,然后进行混合量子力学/分子力学(QM/MM)细化和100 ns分子动力学(MD)模拟,采用主成分分析(PCA)和MM- pbsa结合自由能计算来评估结合相互作用和配合物稳定性。对接发现槲皮素、匹诺曹皮素和柚皮素为最佳结合物,结合能分别为-8.3、-8.1和-8.0 kcal/mol。这些类黄酮铅还表现出良好的药代动力学特性,包括高预测胃肠道吸收、高效清除和最小毒性风险(无致癌或器官特异性警报)。值得注意的是,在100 ns MD模拟中,匹诺松蛋白复合物表现出最大的稳定性,保持紧密结合的构象。总之,槲皮素、皮诺松素和柚皮素是有前途的ZIKV E蛋白抑制剂,具有强大的靶点结合和良好的药物样谱。它们作为抗病毒候选药物的巨大翻译潜力值得进一步的体外和体内研究来证实其有效性和安全性。
{"title":"Evaluation of Potential Inhibitors of Zika Virus Envelope Protein Through Molecular Docking and Molecular Dynamics Simulation","authors":"Jehad Zuhair Tayyeb ,&nbsp;Maria Karolaynne da Silva ,&nbsp;Aamal A. Al-Mutairi ,&nbsp;Hanan M. Alharbi ,&nbsp;Alaa A. Khojah ,&nbsp;Imren Bayıl ,&nbsp;Abdullah Yahya Abdullah Alzahrani ,&nbsp;Zsolt Tóth ,&nbsp;Jonas Ivan Nobre Oliveira ,&nbsp;Magdi E.A. Zaki","doi":"10.1016/j.virusres.2025.199630","DOIUrl":"10.1016/j.virusres.2025.199630","url":null,"abstract":"<div><div>Zika virus (ZIKV) infection remains a global health threat with no approved antivirals or vaccines to date, creating an urgent need for therapeutics targeting ZIKV. The viral envelope (E) protein is critical for host cell entry and represents a validated target for antiviral intervention. Here, we aimed to identify natural flavonoid compounds capable of inhibiting the ZIKV E protein using a dual-phase <em>in silico</em> screening strategy. First, we performed density functional theory (DFT) calculations to optimize the structures of nine candidate flavonoids and obtain quantum chemical descriptors (electronic properties); we also evaluated their drug-likeness and ADMET profiles. Second, we conducted molecular docking of these optimized flavonoids to the E protein, followed by hybrid quantum mechanics/molecular mechanics (QM/MM) refinement and 100 ns molecular dynamics (MD) simulations with principal component analysis (PCA) and MM-PBSA binding free energy calculations to assess binding interactions and complex stability. Docking identified quercetin, pinocembrin, and naringenin as the top binders, with binding energies of –8.3, –8.1, and –8.0 kcal/mol, respectively. These lead flavonoids also exhibited favorable pharmacokinetic properties, including high predicted gastrointestinal absorption, efficient clearance, and minimal toxicity risk (no carcinogenic or organ-specific alerts). Notably, pinocembrin’s complex demonstrated the greatest stability throughout a 100 ns MD simulation, maintaining a tightly bound conformation. In conclusion, quercetin, pinocembrin, and naringenin emerge as promising ZIKV E protein inhibitors with robust target engagement and favorable drug-like profiles. Their significant translational potential as antiviral candidates warrants further <em>in vitro</em> and <em>in vivo</em> studies to confirm efficacy and safety.</div></div>","PeriodicalId":23483,"journal":{"name":"Virus research","volume":"361 ","pages":"Article 199630"},"PeriodicalIF":2.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Virus research
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