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Applications and limitations of respiratory virus infection models in well-differentiated airway epithelial cell cultures of livestock 呼吸道病毒感染模型在家畜高分化气道上皮细胞培养中的应用和局限性
IF 5.1 2区 医学 Q1 VIROLOGY Pub Date : 2025-09-01 DOI: 10.1016/j.coviro.2025.101478
Nora M Gerhards, Luca Bordes, Manouk Vrieling, Rineke de Jong, Rik L de Swart
Development of multispecies well-differentiated airway epithelial cell (WD-AEC) models derived from either primary cells or airway organoids has led to novel options for in vitro characterization of host–pathogen interactions for viruses associated with the respiratory disease complex in livestock. Whereas assessment of adaptive immune responses to infection or vaccination currently still requires studies in animals, viral host restriction, tropism, entry, replication, virulence, and innate host responses of the respiratory epithelium can effectively be studied in WD-AEC cultures. Moreover, these models are also suitable for highly sensitive isolation of field strains of respiratory viruses that can replicate to relatively high titers without relying on multiple passages to generate adequate virus stocks with reduced risk of cell-culture adaptations compared to passaging in immortalized cell lines. In this review, we provide a brief overview of currently available methods and potential model applications.
源自原代细胞或气道类器官的多物种良好分化气道上皮细胞(WD-AEC)模型的发展,为家畜呼吸道疾病相关病毒的宿主-病原体相互作用的体外表征提供了新的选择。虽然评估对感染或疫苗接种的适应性免疫反应目前仍需要在动物身上进行研究,但可以在WD-AEC培养物中有效地研究呼吸道上皮的病毒宿主限制、趋向性、进入、复制、毒力和先天宿主反应。此外,这些模型也适用于高度敏感的呼吸道病毒野毒株的分离,这些病毒株可以复制到相对较高的滴度,而不依赖于多次传代来产生足够的病毒库存,与在永活细胞系中传代相比,细胞培养适应的风险降低。在这篇综述中,我们简要概述了目前可用的方法和潜在的模型应用。
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引用次数: 0
Status of advanced respiratory syncytial virus antiviral therapeutics 2025 晚期呼吸道合胞病毒抗病毒治疗的现状2025
IF 5.1 2区 医学 Q1 VIROLOGY Pub Date : 2025-08-22 DOI: 10.1016/j.coviro.2025.101477
Claire E Ruckel, Josef D Wolf, Richard K Plemper
Respiratory syncytial virus (RSV) causes major morbidity and mortality in vulnerable populations. In infants, RSV infection is a leading cause of hospitalization and can result to severe respiratory complications marked by bronchiolitis and viral pneumonia. Currently, prophylaxis exists in the form of three licensed vaccines, all approved for adults aged >65 years or pregnant women, but no vaccination is available specifically for infants. Prophylactic monoclonal antibody treatments, palivizumab and nirsevimab, are recommended in some instances for newborns, but treatment cost and need for intravenous administration limit universal accessibility. The only antiviral approved for the RSV indication, ribavirin, is no longer recommended for clinical use, creating an urgent need for a novel generation of effective therapeutics. Extensive anti-RSV drug discovery efforts have long been dominated by viral entry inhibitors that emerged as pharmacodominant in automated drug discovery campaigns, yet more recently developed candidates have expanded the target range to the viral polymerase complex and nucleoprotein. Focusing on advanced therapeutic candidates and investigational drugs that have entered clinical trials, this review will discuss challenges in RSV drug development in perspective of recent breakthroughs in RSV prophylaxis, assess the current stage of RSV therapeutic candidates, and identify key requirements for future improved RSV disease management.
呼吸道合胞病毒(RSV)在脆弱人群中引起主要发病率和死亡率。在婴儿中,呼吸道合胞病毒感染是住院的主要原因,并可导致以细支气管炎和病毒性肺炎为特征的严重呼吸道并发症。目前,预防措施以三种许可疫苗的形式存在,所有疫苗都被批准用于65岁以上的成年人或孕妇,但没有专门针对婴儿的疫苗。预防性单克隆抗体治疗,帕利珠单抗和尼塞维单抗,在某些情况下被推荐用于新生儿,但治疗费用和静脉给药的需要限制了普遍可及性。唯一被批准用于RSV适应症的抗病毒药物利巴韦林已不再推荐用于临床,因此迫切需要新一代有效的治疗方法。长期以来,广泛的抗rsv药物发现工作一直由病毒进入抑制剂主导,这些抑制剂在自动药物发现活动中作为药物优势出现,但最近开发的候选药物已将靶标范围扩大到病毒聚合酶复合物和核蛋白。本综述将重点关注已进入临床试验的先进候选治疗药物和研究药物,从RSV预防的最新突破角度讨论RSV药物开发面临的挑战,评估当前阶段的RSV候选治疗药物,并确定未来改进RSV疾病管理的关键要求。
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引用次数: 0
Human organoid models to study coronavirus infections of the respiratory tract 人类类器官模型用于研究冠状病毒呼吸道感染
IF 5.7 2区 医学 Q1 VIROLOGY Pub Date : 2025-07-22 DOI: 10.1016/j.coviro.2025.101476
Merel R te Marvelde , Laura LA van Dijk , Mark A Power , Melanie Rissmann, Rory D de Vries, Bart L Haagmans
The coronavirus disease 2019 (COVID-19) pandemic emphasized the need to study coronaviruses more thoroughly. Next to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), humans can be infected by SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), and various seasonal coronaviruses. It is likely that all human coronaviruses have a zoonotic origin and circulated in animal reservoirs before crossing the species barrier into humans. Historically, these viruses have been investigated in vitro and in vivo, mainly utilizing immortalized cell lines and animal models, respectively. Recently, more advanced physiological model systems have been developed to study coronavirus host interactions, with human organoids serving as innovative in vitro tissue culture system that closely mimics human physiology. Organoids provide a promising platform for investigating coronavirus infections, exploring viral tropism, studying host immune responses, and evaluating potential therapeutic interventions. This review explores the origins and use of airway organoids in studying coronaviruses. Additionally, it outlines prospects for leveraging airway organoids for examination of both innate and adaptive immune responses, evaluation of antiviral drugs, and creating intricate co-culture models for enhanced insight into coronavirus infections of the respiratory tract.
2019冠状病毒病(COVID-19)大流行强调了更彻底研究冠状病毒的必要性。除严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)外,人类还可感染SARS-CoV、中东呼吸综合征冠状病毒(MERS-CoV)和各种季节性冠状病毒。很可能所有人类冠状病毒都有人畜共患起源,并在跨越物种屏障进入人类之前在动物宿主中传播。从历史上看,这些病毒已经在体外和体内进行了研究,主要分别利用永生化细胞系和动物模型。近年来,人们开发出了更先进的生理模型系统来研究冠状病毒与宿主的相互作用,其中人类类器官作为一种创新的体外组织培养系统,与人体生理非常接近。类器官为研究冠状病毒感染、探索病毒趋向性、研究宿主免疫反应和评估潜在的治疗干预措施提供了一个很有前景的平台。本文综述了呼吸道类器官的起源及其在冠状病毒研究中的应用。此外,它概述了利用气道类器官检查先天和适应性免疫反应、评估抗病毒药物以及创建复杂的共培养模型以增强对呼吸道冠状病毒感染的了解的前景。
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引用次数: 0
Illuminating druggable dark matter in RNA virus replication using in situ cryo-EM 利用原位冷冻电镜阐明RNA病毒复制中的可药物暗物质
IF 5.7 2区 医学 Q1 VIROLOGY Pub Date : 2025-07-09 DOI: 10.1016/j.coviro.2025.101475
Himanshu Sharma , Marie N Sorin , Kiran B Sharma , Lars-Anders Carlson
Viral proteins typically exist in the context of complex virions or in the even more complex host cells in which they replicate. Hence, meaningful insights into virus protein structure often need to account for this context. Various flavors of in situ cryo-electron microscopy (cryo-EM), such as cryo-electron tomography, are key methods for the contextual study of virus protein structure in pleomorphic virions and host cells. Here, we review recent in situ cryo-EM work on three selected phenomena in RNA virus replication: the maturation and nuclear entry of HIV-1, the membrane-bound replication organelles of positive-sense RNA viruses, and the membrane-less viral factories of negative-sense RNA viruses. We highlight cases where the imaged phenomena are targets of novel antiviral drugs (such as the recently approved antiretroviral Lenacapavir), drug candidates, and antiviral strategies. Finally, we discuss recent technical advances that extend the reach of in situ cryo-EM in virology.
病毒蛋白通常存在于复杂病毒粒子的环境中,或者在更复杂的宿主细胞中进行复制。因此,对病毒蛋白质结构的有意义的见解往往需要考虑到这一背景。各种形式的原位冷冻电子显微镜(cryo-EM),如冷冻电子断层扫描,是多形性病毒粒子和宿主细胞中病毒蛋白结构背景研究的关键方法。在这里,我们回顾了最近在原位冷冻电镜下对RNA病毒复制的三种选择现象的研究:HIV-1的成熟和核进入,正义RNA病毒的膜结合复制细胞器,以及负义RNA病毒的无膜病毒工厂。我们重点介绍了成像现象是新型抗病毒药物(如最近批准的抗逆转录病毒药物Lenacapavir)、候选药物和抗病毒策略的靶标的病例。最后,我们讨论了最近的技术进展,扩大了原位冷冻电镜在病毒学中的应用范围。
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引用次数: 0
Editorial overview: Viruses and cancer — challenges, breakthroughs, and future directions 编辑概述:病毒和癌症-挑战,突破,和未来的方向
IF 5.7 2区 医学 Q1 VIROLOGY Pub Date : 2025-07-05 DOI: 10.1016/j.coviro.2025.101474
Luca D Bertzbach , Nicole Fischer , Benedikt B Kaufer
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引用次数: 0
State-of-the-art in oncolytic virotherapy using adenoviruses other than the commonly applied adenovirus type 5 除常用的5型腺病毒外,使用腺病毒进行溶瘤病毒治疗的最新进展
IF 5.7 2区 医学 Q1 VIROLOGY Pub Date : 2025-06-27 DOI: 10.1016/j.coviro.2025.101472
Katrin Schröer , Lotta Fiege , Alina Wolf , Vesna Bjelic-Radisic , Anja Ehrhardt
In most clinical trials, oncolytic viruses (OAds) based on human adenovirus type 5 (HAdV-C5) were explored, and only rarely a complete switch to another adenovirus type was evaluated. This review highlights the broader diversity of human adenoviruses and discusses advances in engineering non-HAdV-C5 OAds. We will discuss ongoing research to refine adenoviral constructs derived from alternative adenovirus species, including chimeric viruses, to optimize viral delivery and enhance antitumor immune responses. We summarize translational and clinical studies using these alternative OAds, emphasizing their therapeutic promise despite remaining challenges. Unlocking the full potential of diverse OAds could significantly expand cancer treatment options.
在大多数临床试验中,基于人类腺病毒5型(HAdV-C5)的溶瘤病毒(OAds)被探索,很少评估完全转换为另一种腺病毒类型。这篇综述强调了人类腺病毒的广泛多样性,并讨论了非hadv - c5 oad的工程进展。我们将讨论正在进行的研究,以改进从其他腺病毒物种衍生的腺病毒结构,包括嵌合病毒,以优化病毒传递和增强抗肿瘤免疫反应。我们总结了使用这些替代oad的转化和临床研究,强调了它们的治疗前景,尽管仍然存在挑战。释放各种oad的全部潜力可以显著扩大癌症治疗选择。
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引用次数: 0
Molecules to spillover: how climate warming impacts mosquito-borne viruses 分子溢出:气候变暖如何影响蚊媒病毒
IF 5.7 2区 医学 Q1 VIROLOGY Pub Date : 2025-06-25 DOI: 10.1016/j.coviro.2025.101473
Isabel O Delwel , Erin A Mordecai
Climate change is a critical driver in the outbreaks of vector-borne infectious diseases worldwide. Arbovirus vectors, namely, mosquitoes, exhibit strong and nonlinear responses to climatic factors, such as temperature driving changes in infectious disease dynamics. In this review, we highlight key climate change factors that can affect arboviruses and their mosquito vectors across multiple biological levels, emphasizing the consequences for the transmission and spread of viruses impacting human hosts. We examine the complex interplay between environmental changes and vector biology, including life history traits, vector competence, and species interactions. We characterize vector ecology across scales critical for our understanding of forecasting the impacts of climate change on mosquito-borne viruses, predicting disease outbreaks and developing effective control measures.
气候变化是全世界媒介传播传染病暴发的一个关键驱动因素。虫媒病毒载体,即蚊子,对气候因素表现出强烈的非线性反应,例如传染病动力学中温度驱动的变化。在这篇综述中,我们强调了气候变化在多个生物学水平上影响虫媒病毒及其蚊媒的关键因素,强调了影响人类宿主的病毒传播和传播的后果。我们研究了环境变化和媒介生物学之间复杂的相互作用,包括生活史特征、媒介能力和物种相互作用。我们描述了跨尺度的媒介生态学,这对我们预测气候变化对蚊媒病毒的影响、预测疾病爆发和制定有效的控制措施至关重要。
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引用次数: 0
Ex vivo culture models to study viral infections of the liver 体外培养模型研究肝脏病毒感染
IF 5.7 2区 医学 Q1 VIROLOGY Pub Date : 2025-04-01 DOI: 10.1016/j.coviro.2025.101462
Esther Föderl-Höbenreich, Katrin Panzitt
Ex vivo liver culture models, particularly three-dimensional (3D) models, are vital for studying viral infections of the liver, as they replicate the complex microenvironment more accurately than traditional two-dimensional cultures. These models are essential for understanding viral pathogenesis, replication, and host responses, which are crucial for developing antiviral therapies. Here, we review various ex vivo liver culture models, including primary human hepatocytes (PHHs), liver-on-a-chip, organoids, and precision-cut liver slices. Each model has unique advantages and limitations. For instance, PHHs maintain physiological characteristics but have a limited lifespan, while liver-on-a-chip systems enable dynamic studies but require advanced engineering. Despite challenges in translating findings to human disease, these 3D models hold promise for advancing liver disease research and drug development. Future research should focus on expanding the scope of these models to include a wider range of viruses and improving their physiological relevance to better mimic in vivo conditions.
离体肝脏培养模型,特别是三维(3D)模型,对于研究肝脏病毒感染至关重要,因为它们比传统的二维培养更准确地复制复杂的微环境。这些模型对于理解病毒的发病机制、复制和宿主反应至关重要,这对于开发抗病毒治疗至关重要。在这里,我们回顾了各种离体肝脏培养模型,包括原代人肝细胞(PHHs)、肝脏芯片、类器官和精确切割的肝脏切片。每种模式都有其独特的优点和局限性。例如,phh保持生理特性,但寿命有限,而肝脏芯片系统可以进行动态研究,但需要先进的工程技术。尽管在将研究结果转化为人类疾病方面存在挑战,但这些3D模型有望推动肝病研究和药物开发。未来的研究应侧重于扩大这些模型的范围,以包括更广泛的病毒,并提高它们的生理相关性,以更好地模拟体内条件。
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引用次数: 0
The liver as a potential gate to the brain for encephalitic viruses 肝脏是脑炎病毒进入大脑的潜在通道
IF 5.7 2区 医学 Q1 VIROLOGY Pub Date : 2025-04-01 DOI: 10.1016/j.coviro.2025.101463
Alexandre Lalande , Lola Canus , Amélie Bourgeais, Cyrille Mathieu, Eva Ogire
To model infection of viruses targeting the liver and the central nervous system, two-dimensional in vitro cultures rapidly show their limitations. Conversely, in vivo models do not easily allow the investigation of early events of the infection process. In between, ex vivo models, comprising mainly organoids and organotypic cultures, mimic or retain the cytoarchitecture of the organ while being relatively simple to handle and analyze. Here, we summarize the main features of brain and liver ex vivo models and pinpoint examples of their utilization for studying encephalitogenic and hepatotropic viruses. We highlight a gap of development and application of liver compared to ex vivo models in virology. Many hepatotropic viruses can also infect and/or have impacts on the central nervous system. In this sense, we sought to present these ex vivo models while providing a conceptual framework for the modeling of the hepatocerebral axis in the context of viral infections.
为了模拟针对肝脏和中枢神经系统的病毒感染,二维体外培养迅速显示出其局限性。相反,体内模型不容易允许调查感染过程的早期事件。在这两者之间,主要由类器官和器官型培养物组成的离体模型模拟或保留了器官的细胞结构,同时相对简单地处理和分析。在此,我们总结了脑和肝离体模型的主要特点,并列举了它们在研究致脑性和嗜肝性病毒方面的应用实例。我们强调了肝脏在病毒学方面的发展和应用与离体模型相比的差距。许多嗜肝病毒也可感染和/或影响中枢神经系统。从这个意义上说,我们试图提出这些离体模型,同时为病毒感染背景下的肝脑轴建模提供一个概念框架。
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引用次数: 0
Recent advances in animal models of lymphomagenesis caused by human γ-herpesviruses 人类γ-疱疹病毒所致淋巴瘤动物模型的最新进展
IF 5.7 2区 医学 Q1 VIROLOGY Pub Date : 2025-03-26 DOI: 10.1016/j.coviro.2025.101461
Christian Münz
The two human γ-herpesviruses Epstein Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) cause around 2–3% of all cancers in man. Their exclusive tropism for humans and associated lack of small animal models has impeded the dissection of individual viral gene contributions to tumor formation and of protection by distinct immune responses that are observed in virus carriers. Mice with reconstituted human immune systems (humanized mice) now offer the possibility to study these questions and to develop adoptive antibody and T cell transfers against EBV- and KSHV-associated pathologies. Based on such protective immune responses, vaccine candidates can then be developed to prophylactically and therapeutically induce immune control, similar to the one that avoids virus-associated pathologies in the vast majority of infected individuals.
两种人类γ-疱疹病毒爱泼斯坦巴尔病毒(EBV)和卡波西肉瘤相关疱疹病毒(KSHV)导致约2-3%的人类癌症。它们对人类的专一性和相关小动物模型的缺乏阻碍了对单个病毒基因对肿瘤形成的贡献和在病毒携带者中观察到的独特免疫反应的保护的解剖。具有重组人类免疫系统的小鼠(人源化小鼠)现在提供了研究这些问题和开发针对EBV和kshv相关病理的过继抗体和T细胞转移的可能性。基于这种保护性免疫反应,然后可以开发候选疫苗,以预防性和治疗性地诱导免疫控制,类似于在绝大多数感染者中避免病毒相关病理的疫苗。
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引用次数: 0
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Current opinion in virology
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