O'Hearn Aileen, Wang Minxiu, Cheng Han, Lear-Rooney Calli M, Koning Katie, Rumschlag-Booms Emily, Varhegyi Elizabeth, Olinger Gene, Rong Lijun
Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA.
J Virol. 2015 May;89(10):5441-9. doi: 10.1128/JVI.03689-14. Epub 2015 Mar 4.
UNLABELLED: Filoviruses, including both Ebola virus (EBOV) and Marburg virus (MARV), can infect humans and other animals, causing hemorrhagic fever with a high mortality rate. Entry of these viruses into the host is mediated by a single filoviral glycoprotein (GP). GP is composed of two subunits: GP1, which is responsible for attachment and binding to receptor(s) on susceptible cells, and GP2, which mediates viral and cell membrane fusion. Although numerous host factors have been implicated in the entry process, the initial attachment receptor(s) has not been well defined. In this report, we demonstrate that exostosin 1 (EXT1), which is involved in biosynthesis of heparan sulfate (HS), plays a role in filovirus entry. Expression knockdown of EXT1 by small interfering RNAs (siRNAs) impairs GP-mediated pseudoviral entry and that of infectious EBOV and MARV in tissue cultured cells. Furthermore, HS, heparin, and other related glycosaminoglycans (GAGs), to different extents, can bind to and block GP-mediated viral entry and that of infectious filoviruses. These results strongly suggest that HS and other related GAGs are attachment receptors that are utilized by filoviruses for entry and infection. These GAGs may have therapeutic potential in treating EBOV- and MARV-infected patients. IMPORTANCE: Infection by Ebola virus and Marburg virus can cause severe illness in humans, with a high mortality rate, and currently there is no FDA-approved vaccine or therapeutic treatment available. The ongoing 2014 outbreak in West Africa underscores a lack of our understanding in the infection and pathogenesis of these viruses and the urgency of drug discovery and development. In this study, we provide several pieces of evidence that demonstrate that heparan sulfate and other closely related glycosaminoglycans are the molecules that are used by filoviruses for initial attachment. Furthermore, we demonstrate that these glycosaminoglycans can block entry of and infection by filoviruses. Thus, this work provides mechanistic insights on the early step of filoviral infection and suggests a possible therapeutic option for diseases caused by filovirus infection.
未标记：丝状病毒，包括埃博拉病毒（EBOV）和马尔堡病毒（MARV），可感染人类和其他动物，引发死亡率很高的出血热。这些病毒进入宿主是由单一的丝状病毒糖蛋白（GP）介导的。GP由两个亚基组成：GP1负责与易感细胞上的受体结合，GP2介导病毒与细胞膜融合。尽管众多宿主因子与进入过程有关，但最初的附着受体尚未明确界定。在本报告中，我们证明参与硫酸乙酰肝素（HS）生物合成的外切糖苷酶1（EXT1）在丝状病毒进入过程中起作用。通过小干扰RNA（siRNA）敲低EXT1的表达会损害GP介导的假病毒进入以及组织培养细胞中传染性埃博拉病毒和马尔堡病毒的进入。此外，HS、肝素和其他相关糖胺聚糖（GAG）在不同程度上可结合并阻断GP介导的病毒进入以及传染性丝状病毒的进入。这些结果强烈表明，HS和其他相关GAG是丝状病毒用于进入和感染的附着受体。这些GAG在治疗埃博拉病毒和马尔堡病毒感染患者方面可能具有治疗潜力。 重要性：埃博拉病毒和马尔堡病毒感染可导致人类严重疾病，死亡率很高，目前尚无美国食品药品监督管理局批准的疫苗或治疗方法。2014年在西非爆发的疫情凸显了我们对这些病毒的感染和发病机制缺乏了解以及药物研发的紧迫性。在本研究中，我们提供了几条证据，证明硫酸乙酰肝素和其他密切相关的糖胺聚糖是丝状病毒用于初始附着的分子。此外，我们证明这些糖胺聚糖可阻断丝状病毒的进入和感染。因此，这项工作为丝状病毒感染的早期步骤提供了机制性见解，并为丝状病毒感染引起的疾病提出了一种可能的治疗选择。
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