疾病综述：埃博拉出血热

埃博拉出血热是一种严重的出血性疾病,由某一种埃博拉病毒（EBOV）感染引起,其对赤道非洲地区的公共健康构成了很大威胁。对埃博拉病毒的分类、传播方式、致病机制、风险因子、流行病学、诊断、预防、治疗、新药研发管线及治疗靶标进行综述。     

日本科学家成功去除埃博拉病毒毒性有望制成疫苗

东京大学医学科学研究所的科研小组在《美国科学院院报》上发表了一项研究成果：该研究小组成功地通过基因无毒化操作，使导致埃博拉出血热的埃博拉病毒只在特殊的实验用人工细胞中繁殖。埃博拉病毒感染后死亡率高达50％～90％，目前尚无预防疫苗与治疗药物。研究小组从埃博拉病毒拥有的8个基因中只去除了病毒繁殖必需的“VP30”基因，从而制成了无毒病毒。该无毒病毒仅在注人了“VP30”基因的猴子细胞中进行繁殖，在普通细胞中既不繁殖也不发挥毒性。除此之外，该病毒的外观及性质与原来的埃博拉病毒并无任何区别，     

埃博拉病毒疫苗研究进展

埃博拉出血热是埃博拉病毒(Ebola virus,EBOV)引起的人类和非人灵长类动物急性出血性传染病,目前尚无治疗药物和疫苗获得批准.科研人员正在进行EBOV疫苗的研发,包括病毒样颗粒疫苗、DNA疫苗和病毒载体疫苗等.虽然这些疫苗的免疫机制各不相同,但部分疫苗在非人灵长类动物中能有效对抗EBOV,提示有望成功研制出EBOV疫苗.     

埃博拉出血热诊疗方案（摘录）

埃博拉出血热是由埃博拉病毒引起的一种急性传染病,病死率高,目前在西非流行的扎伊尔型病死率为53%。现将埃博拉出血热的诊疗方案（2014年第1版）要点介绍如下： 一、病原学 埃博拉病毒属丝状病毒科,为不分节段的单股负链RNA病毒,可分为本迪布焦型、扎伊尔型、莱斯顿型、苏丹型和塔伊森林型。其中扎伊尔型毒力最强,苏丹型次之,莱斯顿型对人不致病。     

医学前沿

正我国科学家发现埃博拉病毒入侵人体原理近日,中科院微生物所宣布,该所高福院士团队率先在世界上发现埃博拉病毒入侵人体机制,这将为目前尚无特效治疗药物的埃博拉病毒指明药物研发方向。作为国际病毒学领域的一项重大科研突破,该研究成果在国际权威学术期刊《细胞》上在线发表。     

国内埃博拉病毒研究最新动态

对国内埃博拉病毒诊疗检测产品的近期研究成果及相关专利进行总结归纳,旨在为埃博拉病毒检测试剂及治疗药物的进一步开发提供参考。     

干扰埃博拉病毒繁殖突破性进展

美国波士顿大学医学院“全国潜在传染病实验室”专家托马斯·盖斯伯特领导一个团队,选取2组恒河猕猴应用这种试验性药物。美国研究者利用微粒状基因物质干扰埃博拉病毒繁殖的研究取得突破性进展。实验室研究表明,感染埃博拉病毒的恒河猕猴接受一种试验性药物治疗后死亡率降低。     

冷静对待埃博拉病毒病

埃博拉病毒病（过去称“埃博拉出血热”）是一种烈性传染病,这次爆发迄今已有5500余人受感染,超过2500人死亡。也就是说一旦感染这种病毒,有半数以上的患者不能被救活。据此,民众对这种疾病的恐惧和不安也是可以理解的。今年发生埃博拉病毒病大流行的国家主要是西非四国,即几内亚、利比里亚、塞拉利昂和尼日利亚。到目前为止,英国、瑞士报道过输入病例,输入病例均到流行区旅行过。     

埃博拉病毒病的治疗及新药研究进展

埃博拉病毒是世界上最具威胁的病原体之一,2013年12月始于西非几内亚的埃博拉病毒病（Ebola virus disease,EVD）疫情,成为有记载以来最严重的一次暴发。由于对疫情的估计不足以及缺乏有效的治疗药物,本次疫情的防治效果并不乐观。美国FDA紧急批准了未经系统研究的ZMapp和TKM-Ebola用于埃博拉病毒病的治疗,但限于未知的疗效、安全性和产能的不足,意义有限。本文综述了现有的治疗埃博拉病毒病的方法以及新药的最新研究进展,方便相关人员了解此方面的信息。     

Niemann-Pick C1蛋白在埃博拉病毒感染中的作用及其靶向药物研究进展

埃博拉病毒属丝状病毒科,具有高传染性,能引起人类和灵长类动物出现严重出血热等症状,病死率高达90%。Niemann-Pick C1(NPC1)蛋白是埃博拉病毒感染过程中表达于宿主细胞内体膜上的一个重要受体,其与埃博拉病毒被组织蛋白酶裂解的糖蛋白（GP）的相互作用是病毒感染宿主的关键环节,介导病毒囊膜与内体膜的融合,进而将病毒基因组释放到宿主细胞。近年来,将NPC1蛋白作为广谱抗丝状病毒药物靶点研发的小分子抑制剂、单克隆抗体和基因治疗药物均有突破性进展。本文介绍了NPC1的结构及其在埃博拉病毒感染中的作用,并对靶向NPC1的小分子抑制剂、单克隆抗体药物和基因治疗药物的研究现状进行总结。     

Ebola virus: A gap in drug design and discovery ‐ experimental and computational perspective

The Ebola virus, formally known as the Ebola hemorrhagic fever, is an acute viral syndrome causing sporadic outbreaks that have ravaged West Africa. Due to its extreme virulence and highly transmissible nature, Ebola has been classified as a category A bioweapon organism. Only recently have vaccine or drug regimens for the Ebola virus been developed, including Zmapp and peptides. In addition, existing drugs which have been repurposed toward anti‐Ebola virus activity have been re‐examined and are seen to be promising candidates toward combating Ebola. Drug development involving computational tools has been widely employed toward target‐based drug design. Screening large libraries have greatly stimulated research toward effective anti‐Ebola virus drug regimens. Current emphasis has been placed on the investigation of host proteins and druggable viral targets. There is a huge gap in the literature regarding guidelines in the discovery of Ebola virus inhibitors, which may be due to the lack of information on the Ebola drug targets, binding sites, and mechanism of action of the virus. This review focuses on Ebola virus inhibitors, drugs which could be repurposed to combat the Ebola virus, computational methods which study drug–target interactions as well as providing further insight into the mode of action of the Ebola virus.     

Therapy and prophylaxis of Ebola virus infections

The first cases of Ebola hemorrhagic fever were reported from Sudan and Zaire (now Democratic Republic of the Congo) in 1976, but the virus has only received significant attention since 1995. Until recently, the development of therapeutics or vaccines was not considered a priority. The knowledge gained during the past decade on the biology and pathogenesis of Ebola virus has led to the development of therapeutic strategies that are currently being investigated. Considering the aggressive nature of Ebola infections, in particular the rapid and overwhelming viral burdens, early diagnosis will play a significant role in determining the success of any intervention strategy. Advanced understanding of the immune response has produced several vaccine candidates of which a few can be considered for further evaluation. This review will summarize and discuss the current therapeutic and prophylactic strategies for Ebola hemorrhagic fever.     

Identification of an antioxidant small-molecule with broad-spectrum antiviral activity

The highly lethal filoviruses, Ebola and Marburg cause severe hemorrhagic fever in humans and non-human primates. To date there are no licensed vaccines or therapeutics to counter these infections. Identifying novel pathways and host targets that play an essential role during infection will provide potential targets to develop therapeutics. Small molecule chemical screening for Ebola virus inhibitors resulted in identification of a compound NSC 62914. The compound was found to exhibit anti-filovirus activity in cell-based assays and in vivo protected mice following challenge with Ebola or Marburg viruses. Additionally, the compound was found to inhibit Rift Valley fever virus, Lassa virus and Venezuelan equine encephalitis virus in cell-based assays. Investigation of the mechanism of action of the compound revealed that it had antioxidant properties. Specifically, compound NSC 62914 was found to act as a scavenger of reactive oxygen species, and to up-regulate oxidative stress-induced genes. However, four known antioxidant compounds failed to inhibit filovirus infection, thus suggesting that the mechanistic basis of the antiviral function of the antioxidant NSC 62914 may involve modulation of multiple signaling pathways/targets.     

Treatment of lethal Ebola virus infection in mice with a single dose of an S-adenosyl-L-homocysteine hydrolase inhibitor

Ebola Zaire virus causes lethal hemorrhagic fever in humans, for which there is no effective treatment. A variety of adenosine analogues inhibit the replication of Ebola virus in vitro, probably by blocking the cellular enzyme, S-adenosyl-L-homocysteine hydrolase, thereby indirectly limiting methylation of the 5' cap of viral messenger RNA. We previously observed that adult, immunocompetent mice treated thrice daily for 9 days with 2.2-20 mg/kg of an adenosine analogue, carbocyclic 3-deazaadenosine, were protected against lethal Ebola virus challenge. We now report that a single inoculation of 80 mg/kg or less of the same substance, or of 1 mg/kg or less of another analogue, 3-deazaneplanocin A, provides equal or better protection, without causing acute toxicity. One dose of drug given on the first or second day after virus infection reduced peak viremia more than 1000-fold, compared with mock-treated controls, and resulted in survival of most or all animals. Therapy was less effective when administered on the day of challenge, or on the third day postinfection. Single or multiple doses of the same medications suppressed Ebola replication in severe combined immunodeficient mice, but even daily treatment for 15 consecutive days did not eliminate the infection.     

Cyanovirin-N binds to the viral surface glycoprotein,GP1,2 and inhibits infectivity of Ebola virus

Ebola virus (Ebo) causes severe hemorrhagic fever and high mortality in humans. There are currently no effective therapies. Here, we have explored potential anti-Ebo activity of the human immunodeficiency virus (HIV)-inactivating protein cyanovirin-N (CV-N). CV-N is known to potently inhibit the infectivity of a broad spectrum of HIV strains at the level of viral entry. This involves CV-N binding to N-linked high-mannose oligossacharides on the viral glycoprotein gp120. The Ebola envelope contains somewhat similar oligosaccharide constituents, suggesting possible susceptibility to inhibition by CV-N. Our initial results revealed that CV-N had both in vitro and in vivo antiviral activity against the Zaire strain of the Ebola virus (Ebo-Z). Addition of CV-N to the cell culture medium at the time of Ebo-Z infection inhibited the development of viral cytopathic effects (CPEs). CV-N also delayed the death of Ebo-Z-infected mice, both when given as a series of daily subcutaneous injections and when the virus was incubated ex vivo together with CV-N before inoculation into the mice. Furthermore, similar to earlier results with HIV gp120, CV-N bound with considerable affinity to the Ebola surface envelope glycoprotein, GP(1,2). Competition experiments with free oligosaccharides were consistent with the view that carbohydrate-mediated CV-N/GP(1,2) interactions involve oligosaccharides residing on the Ebola viral envelope. Overall, these studies broaden the range of viruses known to be inhibited by CV-N, and further implicate carbohydrate moieties on viral surface proteins as common viral molecular targets for this novel protein.     

The role of antigen-presenting cells in filoviral hemorrhagic fever: gaps in current knowledge

The filoviruses, Ebola virus (EBOV) and Marburg virus (MARV), are highly lethal zoonotic agents of concern as emerging pathogens and potential bioweapons. Antigen-presenting cells (APCs), particularly macrophages and dendritic cells, are targets of filovirus infection in vivo. Infection of these cell types has been proposed to contribute to the inflammation, activation of coagulation cascades and ineffective immune responses characteristic of filovirus hemorrhagic fever. However, many aspects of filovirus–APC interactions remain to be clarified. Among the unanswered questions: What determines the ability of filoviruses to replicate in different APC subsets? What are the cellular signaling pathways that sense infection and lead to production of copious quantities of cytokines, chemokines and tissue factor? What are the mechanisms by which innate antiviral responses are disabled by these viruses, and how may these mechanisms contribute to inadequate adaptive immunity? A better understanding of these issues will clarify the pathogenesis of filoviral hemorrhagic fever and provide new avenues for development of therapeutics.     

Therapeutic options for diseases due to potential viral agents of bioterrorism

The etiologic agents of smallpox and viral hemorrhagic fever have emerged as potential agents of bioterrorism due to their virulence, potential for human to human dissemination and limited strategies for treatment and prevention. Cidofovir has shown significant promise in animal models, and limited case reports in humans are encouraging. Ribavirin is the treatment of choice for certain hemorrhagic fever viral infections, but has no current application to Ebola and Marburg infections. Current vaccine strategies for smallpox are effective, but carry significant risk for complications. Licensed vaccines for hemorrhagic fever viruses are limited to yellow fever, but animal studies are promising. Genomic analysis of the viral pathogen and the animal model response to infection may provide valuable information enabling the development of novel treatment and prevention strategies. Current knowledge of these strategies is reviewed.     

Development of a broad-spectrum antiviral with activity against Ebola virus

We report herein the identification of a small molecule therapeutic, FGI-106, which displays potent and broad-spectrum inhibition of lethal viral hemorrhagic fevers pathogens, including Ebola, Rift Valley and Dengue Fever viruses, in cell-based assays. Using mouse models of Ebola virus, we further demonstrate that FGI-106 can protect animals from an otherwise lethal infection when used either in a prophylactic or therapeutic setting. A single treatment, administered 1 day after infection, is sufficient to protect animals from lethal Ebola virus challenge. Cell-based assays also identified inhibitory activity against divergent virus families, which supports a hypothesis that FGI-106 interferes with a common pathway utilized by different viruses. These findings suggest FGI-106 may provide an opportunity for targeting viral diseases.