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The nucleoside antiviral prodrug remdesivir in treating COVID-19 and beyond with interspecies significance. 核苷类抗病毒前药瑞德西韦治疗COVID-19及其他疾病具有种间意义。
Pub Date : 2021-01-01 Epub Date: 2021-09-07 DOI: 10.1186/s44149-021-00017-5
Daisy Yan, One Hyuk Ra, Bingfang Yan

Infectious pandemics result in hundreds and millions of deaths, notable examples of the Spanish Flu, the Black Death and smallpox. The current pandemic, caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), is unprecedented even in the historical term of pandemics. The unprecedentedness is featured by multiple surges, rapid identification of therapeutic options and accelerated development of vaccines. Remdesivir, originally developed for Ebola viral disease, is the first treatment of COVID-19 (Coronavirus disease 2019) approved by the United States Food and Drug Administration. As demonstrated by in vitro and preclinical studies, this therapeutic agent is highly potent with a broad spectrum activity against viruses from as many as seven families even cross species. However, randomized controlled trials have failed to confirm the efficacy and safety. Remdesivir improves some clinical signs but not critical parameters such as mortality. This antiviral agent is an ester/phosphorylation prodrug and excessive hydrolysis which increases cellular toxicity. Remdesivir is given intravenously, leading to concentration spikes and likely increasing the potential of hydrolysis-based toxicity. This review has proposed a conceptual framework for improving its efficacy and minimizing toxicity not only for the COVID-19 pandemic but also for future ones caused by remdesivir-sensitive viruses.

传染病导致数亿人死亡,著名的例子是西班牙流感、黑死病和天花。当前由SARS-CoV-2(严重急性呼吸综合征冠状病毒2)引起的大流行,即使在大流行的历史上也是前所未有的。前所未有的特点是多次激增,快速确定治疗选择和加速开发疫苗。最初为埃博拉病毒病开发的Remdesivir是美国食品和药物管理局(fda)批准的首个治疗COVID-19(冠状病毒病2019)的药物。体外和临床前研究表明,该治疗剂对7个科甚至跨物种的病毒具有广谱活性。然而,随机对照试验未能证实其有效性和安全性。瑞德西韦改善了一些临床症状,但没有改善关键参数,如死亡率。这种抗病毒药物是一种酯/磷酸化前药,过度水解会增加细胞毒性。瑞德西韦是静脉注射,导致浓度峰值,并可能增加潜在的水解毒性。本综述提出了一个概念性框架,不仅可以用于COVID-19大流行,还可以用于未来由瑞德西韦敏感病毒引起的大流行,以提高其疗效并最小化毒性。
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引用次数: 4
Identification and phylogenetic analysis of two canine coronavirus strains. 两株犬冠状病毒的鉴定及系统发育分析。
Pub Date : 2021-01-01 Epub Date: 2021-07-19 DOI: 10.1186/s44149-021-00013-9
Junji Gan, Ye Tang, Haifeng Lv, Wenbin Xiong, Xiaoyan Tian

Canine coronavirus (CCoV), a member of the genus Alphacoronavirus, is an enveloped, single-stranded positive-sense RNA virus that responsible for gastroenteritis in dogs. In this study, two CCoV isolates were successfully propagated from 53 CCoV-positive clinical specimens by serial passaging in A-72 cells. These two strains, CCoV JS1706 and CCoV JS1712, caused cytopathic effects in A-72 cells. The sizes of virus plaque formed by them differed in early passages. Electron microscopy revealed a large quantity of typical coronavirus particles with 80-120 nm in diameter in cell culture media and cytoplasm of infected cells, in which they appeared as inclusion bodies. RT-PCR analysis of S gene indicated that these two isolates were belonged to CCoV IIa subtype. Homology of RdRp, S, M and N proteins between the two strains were 100, 99.6, 99.2 and 100.0%, respectively, whereas they were 99.4-100%, 83.1-95.2%, 88.5-99.2% and 91.9-99.7% identity compared to CCoV II reference strains. Phylogenetic analysis of RdRp, S, M and N protein showed that they were closely related to CCoV II strains. These two subtype IIa isolates will be useful for evaluating the pathogenesis and evolution of CCoV and for developing diagnostic reagents and vaccines.

犬冠状病毒(CCoV)是一种包膜单链正义RNA病毒,是引起犬肠胃炎的主要原因。本研究通过A-72细胞的连续传代,成功地从53份CCoV阳性临床标本中分离出2株CCoV。CCoV JS1706和CCoV JS1712在A-72细胞中引起细胞病变。它们在早期传代时形成的病毒空斑大小不同。电镜观察发现,在感染细胞的细胞培养基和细胞质中存在大量直径80 ~ 120nm的典型冠状病毒颗粒,颗粒中以包涵体的形式出现。S基因的RT-PCR分析表明,这两株分离株均为冠状病毒IIa亚型。两株RdRp、S、M和N蛋白的同源性分别为100、99.6、99.2和100.0%,而与参考株的同源性分别为99.4-100%、83.1-95.2%、88.5-99.2%和91.9-99.7%。RdRp、S、M和N蛋白的系统发育分析表明,它们与cov II型亲缘关系密切。这两种IIa亚型分离株将有助于评估冠状病毒的发病机制和演变以及开发诊断试剂和疫苗。
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引用次数: 1
Porcine epidemic diarrhea virus nsp14 inhibits NF-κB pathway activation by targeting the IKK complex and p65. 猪流行性腹泻病毒nsp14通过靶向IKK复合物和p65抑制NF-κB通路激活。
Pub Date : 2021-01-01 Epub Date: 2021-10-14 DOI: 10.1186/s44149-021-00025-5
Shasha Li, Fan Yang, Caina Ma, Weijun Cao, Jinping Yang, Zhenxiang Zhao, Hong Tian, Zixiang Zhu, Haixue Zheng

Coronaviruses (CoVs) are a group of related enveloped RNA viruses that have severe consequences in a wide variety of animals by causing respiratory, enteric or systemic diseases. Porcine epidemic diarrhea virus (PEDV) is an economically important CoV distributed worldwide that causes diarrhea in pigs. nsp14 is a nonstructural protein of PEDV that is involved in regulation of innate immunity and viral replication. However, the function and mechanism by which nsp14 modulates and manipulates host immune responses remain largely unknown. Here, we report that PEDV nsp14 is an NF-κB pathway antagonist. Overexpression PEDV nsp14 protein remarkably decreases SeV-, poly (I:C)- and TNF-α-induced NF-κB activation. Meanwhile, expression of proinflammatory cytokines is suppressed by nsp14. nsp14 inhibits the phosphorylation of IKKs by interacting with IKKs and p65. Furthermore, nsp14 suppresses TNF-α-induced phosphorylation and nuclear import of p65. Overexpression nsp14 considerably increases PEDV replication. These results suggest a novel mechanism employed by PEDV to suppress the host antiviral response, providing insights that can guide the development of antivirals against CoVs.

冠状病毒(cov)是一组相关的包膜RNA病毒,通过引起呼吸道、肠道或全身性疾病,对多种动物造成严重后果。猪流行性腹泻病毒(PEDV)是一种经济上重要的冠状病毒,分布在世界各地,引起猪腹泻。nsp14是PEDV的一种非结构蛋白,参与先天性免疫和病毒复制的调控。然而,nsp14调节和操纵宿主免疫反应的功能和机制在很大程度上仍然未知。在这里,我们报道PEDV nsp14是一种NF-κB通路拮抗剂。过表达PEDV nsp14蛋白可显著降低SeV-、poly (I:C)-和TNF-α-诱导的NF-κ b活化。同时,nsp14抑制促炎细胞因子的表达。nsp14通过与IKKs和p65相互作用抑制IKKs的磷酸化。此外,nsp14抑制TNF-α-诱导的p65磷酸化和核输入。过表达nsp14显著增加PEDV的复制。这些结果提示了PEDV抑制宿主抗病毒反应的新机制,为指导针对冠状病毒的抗病毒药物的开发提供了新的见解。
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引用次数: 4
Development of an accurate lateral flow immunoassay for PEDV detection in swine fecal samples with a filter pad design. 基于过滤垫设计的猪粪便中PEDV精确侧流免疫检测方法的开发。
Pub Date : 2021-01-01 Epub Date: 2021-11-08 DOI: 10.1186/s44149-021-00029-1
Siyi Zou, Lei Wu, Gan Li, Juan Wang, Dongni Cao, Tao Xu, Aiqing Jia, Yong Tang

Porcine epidemic diarrhea virus (PEDV), as the main causative pathogen of viral diarrhea in pigs, has been reported to result in high morbidity and mortality in neonatal piglets and cause significant economic losses to the swine industry. Rapid diagnosis methods are essential for preventing outbreaks and transmission of this disease. In this study, a paper-based lateral flow immunoassay for the rapid diagnosis of PEDV in swine fecal samples was developed using stable color-rich latex beads as the label. Under optimal conditions, the newly developed latex bead-based lateral flow immunoassay (LBs-LFIA) attained a limit of detection (LOD) as low as 103.60 TCID50/mL and no cross-reactivity with other related swine viruses. To solve swine feces impurity interference, by adding a filtration unit design of LFIA without an additional pretreatment procedure, the LBs-LFIA gave good agreement (92.59%) with RT-PCR results in the analysis of clinical swine fecal samples (n = 108), which was more accurate than previously reported colloidal gold LFIA (74.07%) and fluorescent LFIA (86.67%). Moreover, LBs-LFIA showed sufficient accuracy (coefficient of variance [CV] < 15%) and stable (room temperature storage life > 56 days) performance for PEDV detection, which is promising for on-site analysis and user-driven testing in pig production system.

Supplementary information: The online version contains supplementary material available at 10.1186/s44149-021-00029-1.

猪流行性腹泻病毒(PEDV)是引起猪病毒性腹泻的主要病原体,据报道可导致新生仔猪的高发病率和死亡率,并给养猪业造成重大经济损失。快速诊断方法对于预防该病的暴发和传播至关重要。本研究建立了一种基于纸张的横向流动免疫分析法,用于猪粪便样品中PEDV的快速诊断,该方法使用稳定的富色乳胶珠作为标签。在最佳条件下,新开发的基于乳胶珠的横向流动免疫分析法(LBs-LFIA)的检出限(LOD)低至103.60 TCID50/mL,与其他相关猪病毒无交叉反应性。为了解决猪粪杂质干扰问题,通过添加LFIA过滤单元设计,无需额外预处理,LFIA -LFIA在临床猪粪便样品(n = 108)分析中与RT-PCR结果吻合良好(92.59%),高于已有报道的胶体金LFIA(74.07%)和荧光LFIA(86.67%)。此外,LBs-LFIA在PEDV检测中表现出足够的准确性(方差系数[CV] 56天),有望用于养猪生产系统的现场分析和用户驱动检测。补充信息:在线版本包含补充信息,获取地址:10.1186/s44149-021-00029-1。
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引用次数: 2
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动物疾病(英文)
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