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Jimmy Kapetshi, Hugues Fausther-Bovendo, Cindi Corbett, Anders Leung, Kamal Ait-Ikhlef, Justus Nsio, Aaron Aruna, Benoit Kebela Ilunga, Jean-Jacques Muyembe, Pierre Formenty, Gary P Kobinger
Detection of chains of transmission is critical to interrupt Ebola virus (EBOV) outbreaks. For >25 years, quantitative reverse transcription polymerase chain reaction performed on biological fluids has been the reference standard for EBOV detection and identification. In the current study, we investigated the use of environmental sampling to detect EBOV shed from probable case patients buried without the collection of bodily fluids. During the 2012 Bundibugyo virus (BDBV) outbreak in the Democratic Republic of the Congo, environmental samples were screened for BDBV RNA by means of real-time polymerase chain reaction...
October 16, 2018: Journal of Infectious Diseases
Ami Patel, Emma L Reuschel, Kimberly A Kraynyak, Trina Racine, Daniel H Park, Veronica L Scott, Jonathan Audet, Dinah Amante, Megan C Wise, Amelia A Keaton, Gary Wong, Daniel O Villarreal, Jewell Walters, Kar Muthumani, Devon J Shedlock, Marc-Antoine de La Vega, Ross Plyler, Jean Boyer, Kate E Broderick, Jian Yan, Amir S Khan, Shane Jones, Alexander Bello, Geoff Soule, Kaylie N Tran, Shihua He, Kevin Tierney, Xiangguo Qiu, Gary P Kobinger, Niranjan Y Sardesai, David B Weiner
Background: There remains an important need for prophylactic anti-Ebola virus vaccine candidates that elicit long-lasting immune responses and can be delivered to vulnerable populations that are unable to receive live-attenuated or viral vector vaccines. Methods: We designed novel synthetic anti-Ebola virus glycoprotein (EBOV-GP) DNA vaccines as a strategy to expand protective breadth against diverse EBOV strains and evaluated the impact of vaccine dosing and route of administration on protection against lethal EBOV-Makona challenge in cynomolgus macaques...
October 10, 2018: Journal of Infectious Diseases
Jingru Fang, Colette Pietzsch, Palaniappan Ramanathan, Rodrigo I Santos, Philipp A Ilinykh, Mariano A Garcia-Blanco, Alexander Bukreyev, Shelton S Bradrick
Ebola virus (EBOV) genome and mRNAs contain long, structured regions that could hijack host RNA-binding proteins to facilitate infection. We performed RNA affinity chromatography coupled with mass spectrometry to identify host proteins that bind to EBOV RNAs and identified four high-confidence proviral host factors, including Staufen1 (STAU1), which specifically binds both 3' and 5' extracistronic regions of the EBOV genome. We confirmed that EBOV infection rate and production of infectious particles were significantly reduced in STAU1-depleted cells...
October 9, 2018: MBio
Gian Luca Daino, Aldo Frau, Cinzia Sanna, Daniela Rigano, Simona Distinto, Veronica Madau, Francesca Esposito, Elisa Fanunza, Giulia Bianco, Orazio Taglialatela-Scafati, Luca Zinzula, Elias Maccioni, Angela Corona, Enzo Tramontano
The Filoviridae Ebola virus (EBOV) causes a severe and rapidly progressing hemorrhagic syndrome whose recent epidemic enlightened the urgent need of novel therapeutic agents, since no drug is currently approved. A key contribution to EBOV high lethality comes from viral evasion of the host antiviral innate immune response in which the viral protein VP35 plays a crucial role, blocking the interferon type I production, firstly by masking the viral dsRNA and preventing its detection by the pattern recognition receptor RIG-I...
October 9, 2018: Biochemistry
Patrick Younan, Mathieu Iampietro, Rodrigo I Santos, Palaniappan Ramanathan, Vsevolod L Popov, Alexander Bukreyev
The outer leaflet of the viral membrane of Ebola virus (EBOV) virions is enriched with phosphatidylserine (PtdSer), which is thought to play a central role in viral tropism, entry, and virus-associated immune evasion. We investigated the effects of inhibiting synthesis and/or export of PtdSer to the cell surface of infected cells on viral infectivity. Knockdown of both PtdSer synthase enzymes, PTDSS1 and PTDSS2, effectively decreased viral production. Decreased PtdSer expression resulted in an accumulation of virions at the plasma membrane and adjacent of intracellular organelles, suggesting that virion budding is impaired...
October 4, 2018: Journal of Infectious Diseases
Peace Babirye, Carol Musubika, Samuel Kirimunda, Robert Downing, Julian J Lutwama, Edward K Mbidde, Jacqueline Weyer, Janusz T Paweska, Moses L Joloba, Misaki Wayengera
BACKGROUND: Ebolavirus and Marburgvirus are genera of the virus family Filoviridae. Filoviruses cause rare but fatal viral hemorrhagic fevers (VHFs) in remote villages of equatorial Africa with potential for regional and international spread. Point-of-care (POC) rapid diagnostic tests (RDTs) are critical for early epidemic detection, reponse and control. There are 2 RDTs for Zaire ebolavirus (EBOV), but not other Ebolavirus spp. or Marburg marburgvirus (MARV). We validate 3 conserved B cell epitopes of filovirus glycoprotein (GP) using ebola virus diseases (EVD) survivor samples, towards devising pan-filovirus RDTs...
October 3, 2018: BMC Infectious Diseases
Yuan Lin, Chiu-Yueh Hung, Chayanika Bhattacharya, Starr Nichols, Hafsa Rahimuddin, Farooqahmed S Kittur, TinChung Leung, Jiahua Xie
Therapeutic monoclonal antibodies (mAbs) have evolved into an important class of effective medicine in treatment of various diseases. Since the antibody molecule consists of two identical heavy chains (HC) and two light chains (LC), each chain encoded by two different genes, their expressions at similar levels are critical for efficient assembly of functional recombinant mAbs. Although the plant-based expression system has been tested to produce fully assembled recombinant mAbs, coordinately expressing HC and LC at similar levels in a transgenic plant remains a challenge...
2018: Frontiers in Plant Science
Benjamin M Janus, Nydia van Dyk, Xuelian Zhao, Katie A Howell, Cinque Soto, M Javad Aman, Yuxing Li, Thomas R Fuerst, Gilad Ofek
The severity of the 2014-2016 ebolavirus outbreak in West Africa expedited clinical development of therapeutics and vaccines though the countermeasures on hand were largely monospecific and lacked efficacy against other ebolavirus species that previously emerged. Recent studies indicate that ebolavirus glycoprotein (GP) fusion loops are targets for cross-protective antibodies. Here we report the 3.72 Å resolution crystal structure of one such cross-protective antibody, CA45, bound to the ectodomain of Ebola virus (EBOV) GP...
September 26, 2018: Nature Communications
T Fischer, M Spohn, F Olearo, M E Zinser, Rahel Kasonta, H C Stubbe, A Rechtien, M L Ly, S Schmiedel, A W Lohse, A Grundhoff, M M Addo, C Dahlke
VSV-EBOV is a replication-competent Ebola virus (EBOV) vaccine, which was tested in clinical trials as response to the Ebola virus disease (EVD) outbreak 2013-2016. It is the most advanced EBOV candidate currently in the licensure process. The experimental vaccine was again administered as response to outbreaks in the Democratic Republic of Congo. However, underlying molecular mechanisms that convey protection remain incompletely understood. MicroRNAs (miRNAs) are known key regulators that influence gene expression on a post-transcriptional level...
September 21, 2018: Vaccine
Ronald B Reisler, Xiankun Zeng, Christopher W Schellhase, Jeremy J Bearss, Travis K Warren, John C Trefry, George W Christopher, Mark G Kortepeter, Sina Bavari, Anthony P Cardile
In the 2014⁻2016 West Africa Ebola Virus (EBOV) outbreak, there was a significant concern raised about the potential for secondary bacterial infection originating from the gastrointestinal tract, which led to the empiric treatment of many patients with antibiotics. This retrospective pathology case series summarizes the gastrointestinal pathology observed in control animals in the rhesus EBOV-Kikwit intramuscular 1000 plaque forming unit infection model. All 31 Non-human primates (NHPs) exhibited lymphoid depletion of gut-associated lymphoid tissue (GALT) but the severity and the specific location of the depletion varied...
September 20, 2018: Viruses
Nicole A Hoff, Patrick Mukadi, Reena H Doshi, Matthew S Bramble, Kai Lu, Adva Gadoth, Cyrus Sinai, D'Andre Spencer, Bradley P Nicholson, Russell Williams, Matthias Mossoko, Benoit Ilunga-Kebela, Joseph Wasiswa, Emile Okitolonda-Wemakoy, Vivian H Alfonso, Imke Steffen, Jean-Jacques Muyembe-Tamfum, Graham Simmons, Anne W Rimoin
Healthcare settings have played a major role in propagation of Ebola virus (EBOV) outbreaks. Healthcare workers (HCWs) have elevated risk of contact with EBOV-infected patients, particularly if safety precautions are not rigorously practiced. We conducted a serosurvey to determine seroprevalence against multiple EBOV antigens among HCWs of Boende Health Zone, Democratic Republic of the Congo, the site of a 2014 EBOV outbreak. Interviews and specimens were collected from 565 consenting HCWs. Overall, 234 (41...
September 19, 2018: Journal of Infectious Diseases
Olivier Reynard, Evelyne Schaeffer, Valentina A Volchkova, Andrea Cimarelli, Christopher G Mueller, Viktor E Volchkov
The West African outbreak of Ebola virus (EBOV) infection during 2013-2016 highlighted the need for development of field-applicable therapeutic drugs for this infection. Here we report that mannoside glycolipid conjugates (MGCs) consisting of a trimannose head and a lipophilic chain assembled by a linker inhibit EBOV infection not only of human monocyte-derived dendritic cells and macrophages, but also of a number of susceptible cells. Analysis of the mode of action leads us to conclude that MGCs act directly on cells, notably by preventing virus endocytosis...
September 17, 2018: Journal of Infectious Diseases
Qiu-Dong Su, Shi-Hua He, Yao Yi, Feng Qiu, Xue-Xin Lu, Zhi-Yuan Jia, Qing-Ling Meng, Xue-Ting Fan, Rui-Guang Tian, Jonathan Audet, Xiang-Guo Qiu, Sheng-Li Bi
Ebola virus (EBOV) disease (EVD) leads to lethal hemorrhagic fever with a case fatality rate as high as 90%, thus posing a serious global public health concern. However, while several vaccines based on the EBOV glycoprotein have been confirmed to be effective in animal experiments, no licensed vaccines or effective treatments have been approved since the first outbreak was reported in 1976. In this study, we prepared the extracellular domain of the EBOV GP protein (designated as N20) by prokaryotic expression and purification via chromatography...
October 1, 2018: Vaccine
Charles D Murin, Jessica F Bruhn, Zachary A Bornholdt, Jeffrey Copps, Robyn Stanfield, Andrew B Ward
Monoclonal antibodies (mAbs) with pan-ebolavirus cross-reactivity are highly desirable, but development of such mAbs is limited by a lack of a molecular understanding of cross-reactive epitopes. The antibody ADI-15878 was previously identified from a human survivor of Ebola virus Makona variant (EBOV/Mak) infection. This mAb demonstrated potent neutralizing activity against all known ebolaviruses and provided protection in rodent and ferret models against three ebolavirus species. Here, we describe the unliganded crystal structure of ADI-15878 as well as the cryo-EM structures of ADI-15878 in complex with the EBOV/Mak and Bundibugyo virus (BDBV) glycoproteins (GPs)...
September 4, 2018: Cell Reports
Tatiana Ammosova, Colette A Pietzsch, Yasemin Saygideger, Andrey Ilatovsky, Xionghao Lin, Andrey Ivanov, Namita Kumari, Marina Jerebtsova, Amol Kulkarni, Michael Petukhov, Aykut Üren, Alexander Bukreyev, Sergei Nekhai
Background: Ebola virus (EBOV) infection causes severe hemorrhagic fever. EBOV transcription is controlled by host protein phosphatase 1 (PP1), which dephosphorylates VP30 protein. We previously developed 1E7-03, a compound targeting a noncatalytic site of PP1 that induced VP30 phosphorylation and inhibited EBOV transcription. Here, we attempted to further improve 1E7-03, which was not stable in murine serum. Results: High-throughput screening with EBOV-green fluorescent protein was conducted on 72 1E7-03 analogs and identified 6 best inhibitory and the least toxic compounds...
August 28, 2018: Journal of Infectious Diseases
Michelle L Pleet, James Erickson, Catherine DeMarino, Robert A Barclay, Maria Cowen, Benjamin Lepene, Janie Liang, Jens H Kuhn, Laura Prugar, Spencer W Stonier, John M Dye, Weidong Zhou, Lance A Liotta, M Javad Aman, Fatah Kashanchi
Background: Ebola virus (EBOV) mainly targets myeloid cells; however, extensive death of T cells is often observed in lethal infections. We have previously shown that EBOV VP40 in exosomes causes recipient immune cell death. Methods: Using VP40-producing clones, we analyzed donor cell cycle, extracellular vesicle (EV) biogenesis, and recipient immune cell death. Transcription of cyclin D1 and nuclear localization of VP40 were examined via kinase and chromatin immunoprecipitation assays...
August 30, 2018: Journal of Infectious Diseases
Manasi Tamhankar, Dawn M Gerhardt, Richard S Bennett, Nicole Murphy, Peter B Jahrling, Jean L Patterson
BACKGROUND: Currently, no FDA-approved vaccines or treatments are available for Ebola virus disease (EVD), and therapy remains largely supportive. Ebola virus (EBOV) has broad tissue tropism and can infect a variety of cells including epithelial cells. Epithelial cells differ from most other cell types by their polarized phenotype and barrier function. In polarized cells, the apical and basolateral membrane domains are demarcated by tight junctions, and specialized sorting machinery, which results in a difference in composition between the two membrane domains...
August 31, 2018: Virology Journal
Nakyung Lee, David Shum, Alexander König, Hichul Kim, Jinyeong Heo, Saehong Min, Jihye Lee, Yoonae Ko, Inhee Choi, Honggun Lee, Constantin Radu, Thomas Hoenen, Ji-Young Min, Marc P Windisch
The massive epidemic of Ebola virus disease (EVD) in West Africa, followed in recent months by two outbreaks in the Democratic Republic of the Congo, underline the importance of this severe disease. Because Ebola virus (EBOV) must be manipulated under biosafety level 4 (BSL4) containment, the discovery and development of virus-specific therapies have been hampered. Recently, a transient transfection-based transcription- and replication competent virus-like particle (trVLP) system was described, enabling modeling of the entire EBOV life cycle under BSL2 conditions...
October 2018: Antiviral Research
Kuldeep Dhama, Kumaragurubaran Karthik, Rekha Khandia, Sandip Chakraborty, Ashok Munjal, Shyma K Latheef, Deepak Kumar, Muthannan Andavar Ramakrishnan, Yashpal Singh Malik, Rajendra Singh, Satya Veer Singh Malik, Raj Kumar Singh, Wanpen Chaicumpa
Ebola virus (EBOV), a member of the family Filoviridae , is responsible for causing Ebola virus disease (EVD) (formerly named Ebola hemorrhagic fever). This is a severe, often fatal illness with mortality rates varying from 50 to 90% in humans. Although the virus and associated disease has been recognized since 1976, it was only when the recent outbreak of EBOV in 2014-2016 highlighted the danger and global impact of this virus, necessitating the need for coming up with the effective vaccines and drugs to counter its pandemic threat...
2018: Frontiers in Immunology
Eun-Mee Park, Sun-Whan Park, Ye-Ji Lee, Won-Ja Lee, Wooyoung Choi
In this study, we generated recombinant virus-like particles (VLPs) against family Filoviridae, genus Ebolavirus, species Zaire ebolavirus, strain Makona (EBOV) in Drosophila melanogaster Schneider 2 (S2) cells using the EBOV Makona. S2 cells were cotransfected with four viral plasmids encoding EBOV Makona proteins and protein expression was analyzed by immunoblotting. We confirmed that EBOV Makona proteins were successfully expressed in S2 cells. Additionally, we further examined the formation of intracellular and extracellular VLPs by electron microscopy...
November 2018: Journal of Virological Methods
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