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Shambhavi Shubham, Jan Hoinka, Soma Banerjee, Emma Swanson, Jacob A Dillard, Nicholas J Lennemann, Teresa M Przytycka, Wendy Maury, Marit Nilsen-Hamilton
With properties such as stability to long-term storage and amenability to repetitive use, nucleic acid aptamers are compatible with many sensing/transducing platforms intended for use in remote locations. Sensors with these properties are important for quickly identifying ebolavirus outbreaks, which frequently start in locations that lack sophisticated equipment. Soluble glycoprotein (sGP), an excellent biomarker for ebolaviruses, is produced from the same gene as the ebolavirus glycoprotein GP1,2 that decorates the surface of the viral particle and is secreted in abundance into the blood stream even during the early stages of infection...
August 17, 2018: Scientific Reports
Michelle Meyer, Asuka Yoshida, Palaniappan Ramanathan, Erica Ollmann Saphire, Peter L Collins, James E Crowe, Siba Samal, Alexander Bukreyev
Comparative immune response profiling is important for selecting next-generation vaccines. We comprehensively evaluated the antibody responses from a panel of nine respiratory vaccines against Ebola virus (EBOV) derived from human and avian paramyxoviruses expressing EBOV glycoprotein (GP). Most vaccines were protective in guinea pigs but yielded antibody repertoires that differed in proportion targeting key antigenic regions, avidity, neutralizing antibody specificities, and linear epitope preferences. Competition studies with monoclonal antibodies from human survivors revealed that some epitopes in GP targeted for neutralization were vector dependent, while EBOV-neutralizing titers correlated with the response magnitude toward the receptor-binding domain and GP1/GP2 interface epitopes...
August 14, 2018: Cell Reports
Xin Zhang, Qiang Liu, Qianqian Li, Yinghong Li, Zhandong Liu, Hongbin Deng, Sheng Tang, Yanxiang Wang, Youchun Wang, Danqing Song
Twenty-six novel tricyclic sophoridinic and matrinic derivatives containing a common chlorinated benzene fragment were designed, synthesized and evaluated for their anti-ebolavirus (EBOV) activities. Structure-activity relationship analysis indicated: (i) 12 N -dichlorobenzyl motif was beneficial for the activity; (ii) the chiral configuration at C5 atom might not affect the activity much. Among the target compounds, compound 7d exhibited the most potent potency against EBOV with an IC50 value of 5.29 μmol/L and an SI value of over 37...
July 2018: Acta Pharmaceutica Sinica. B
Matthew S Bramble, Nicole Hoff, Pavlo Gilchuk, Patrick Mukadi, Kai Lu, Reena H Doshi, Imke Steffen, Bradly P Nicholson, Allen Lipson, Neerja Vashist, Cyrus Sinai, D'andre Spencer, Garrard Olinger, Emile Okitolonda Wemakoy, Benoit Kebela Illunga, James Pettitt, James Logue, Jonathan Marchand, Justin Varughese, Richard S Bennett, Peter Jahrling, Guy Cavet, Tito Serafini, Erica Ollmann Saphire, Eric Vilain, Jean Jacques Muyembe-Tamfum, Lisa E Hensely, Graham Simmons, James E Crowe, Anne W Rimoin
One year after a Zaire ebolavirus (EBOV) outbreak occurred in the Boende Health Zone of the Democratic Republic of the Congo during 2014, we sought to determine the breadth of immune response against diverse filoviruses including EBOV, Bundibugyo (BDBV), Sudan (SUDV), and Marburg (MARV) viruses. After assessing the 15 survivors, 5 individuals demonstrated some degree of reactivity to multiple ebolavirus species and, in some instances, Marburg virus. All 5 of these survivors had immunoreactivity to EBOV glycoprotein (GP) and EBOV VP40, and 4 had reactivity to EBOV nucleoprotein (NP)...
August 13, 2018: Journal of Infectious Diseases
Erica Ollmann Saphire, Sharon L Schendel, Marnie L Fusco, Karthik Gangavarapu, Bronwyn M Gunn, Anna Z Wec, Peter J Halfmann, Jennifer M Brannan, Andrew S Herbert, Xiangguo Qiu, Kshitij Wagh, Shihua He, Elena E Giorgi, James Theiler, Kathleen B J Pommert, Tyler B Krause, Hannah L Turner, Charles D Murin, Jesper Pallesen, Edgar Davidson, Rafi Ahmed, M Javad Aman, Alexander Bukreyev, Dennis R Burton, James E Crowe, Carl W Davis, George Georgiou, Florian Krammer, Christos A Kyratsous, Jonathan R Lai, Cory Nykiforuk, Michael H Pauly, Pramila Rijal, Ayato Takada, Alain R Townsend, Viktor Volchkov, Laura M Walker, Cheng-I Wang, Larry Zeitlin, Benjamin J Doranz, Andrew B Ward, Bette Korber, Gary P Kobinger, Kristian G Andersen, Yoshihiro Kawaoka, Galit Alter, Kartik Chandran, John M Dye
Antibodies are promising post-exposure therapies against emerging viruses, but which antibody features and in vitro assays best forecast protection are unclear. Our international consortium systematically evaluated antibodies against Ebola virus (EBOV) using multidisciplinary assays. For each antibody, we evaluated epitopes recognized on the viral surface glycoprotein (GP) and secreted glycoprotein (sGP), readouts of multiple neutralization assays, fraction of virions left un-neutralized, glycan structures, phagocytic and natural killer cell functions elicited, and in vivo protection in a mouse challenge model...
August 9, 2018: Cell
Kai J Rogers, Wendy Maury
The filovirus, Zaire Ebolavirus (EBOV), infects tissue macrophages (Mϕs) and dendritic cells (DCs) early during infection. Viral infection of both cells types is highly productive, leading to increased viral load. However, virus infection of these two cell types results in different consequences for cellular function. Infection of Mϕs stimulates the production of proinflammatory and immunomodulatory cytokines and chemokines, leading to the production of a cytokine storm, while simultaneously increasing tissue factor production and thus facilitating disseminated intravascular coagulation...
August 10, 2018: Journal of Leukocyte Biology
Deepak Kumar, Sulgey Gauthami, Madala Uma, Karthika Nagalekshmi, Pavuluri Panduranga Rao, Atanu Basu, Krishna M Ella, Nagendra R Hegde
Ebolavirus (EBOV) is the etiology of Ebola hemorrhagic fever (EHF). A major EHF outbreak in 2014-2015 in West Africa claimed >11,000 lives. A licensed vaccine is not available for EHF, although several vaccines have undergone clinical trials. We developed a human adenovirus (Ad) serotype 5-based candidate EHF vaccine based on controlled expression of the EBOV (Makona strain) glycoprotein (GP) as the immunogen. Two clones, AdGP72 and AdGP75, and a control Ad515 vector, were generated and tested for protein expression in vitro and immunogenicity in mice...
August 10, 2018: Viral Immunology
Bronwyn M Gunn, Wen-Han Yu, Marcus M Karim, Jennifer M Brannan, Andrew S Herbert, Anna Z Wec, Peter J Halfmann, Marnie L Fusco, Sharon L Schendel, Karthik Gangavarapu, Tyler Krause, Xiangguo Qiu, Shinhua He, Jishnu Das, Todd J Suscovich, Jonathan Lai, Kartik Chandran, Larry Zeitlin, James E Crowe, Douglas Lauffenburger, Yoshihiro Kawaoka, Gary P Kobinger, Kristian G Andersen, John M Dye, Erica Ollmann Saphire, Galit Alter
The recent Ebola virus (EBOV) epidemic highlighted the need for effective vaccines and therapeutics to limit and prevent outbreaks. Host antibodies against EBOV are critical for controlling disease, and recombinant monoclonal antibodies (mAbs) can protect from infection. However, antibodies mediate an array of antiviral functions including neutralization as well as engagement of Fc-domain receptors on immune cells, resulting in phagocytosis or NK cell-mediated killing of infected cells. Thus, to understand the antibody features mediating EBOV protection, we examined specific Fc features associated with protection using a library of EBOV-specific mAbs...
August 8, 2018: Cell Host & Microbe
M Anthony Moody
In this issue of Cell Host & Microbe and in a related Cell paper, works by Gunn et al. (2018) and Saphire et al. (2018) describe a large number of monoclonal antibodies against Ebola virus (EBOV) and correlate their activity with in vivo protection.
August 8, 2018: Cell Host & Microbe
Stephanie N Seifert, Jonathan E Schulz, M Jeremiah Matson, Trenton Bushmaker, Andrea Marzi, Vincent J Munster
Sequencing viral genomes during an outbreak can facilitate response and containment efforts. In this study, we describe a reverse transcription long-range polymerase chain reaction for efficient amplification and sequencing of the Ebola virus (EBOV) genome in 2 seminested reactions. We demonstrate that our method remains robust with complex biological samples by amplifying and sequencing the EBOV genome from EBOV-infected nonhuman primates (NHPs). We further demonstrate that we are able to recover viral genomes from starting concentrations as low as 103 50% tissue culture infective dose (TCID50)/mL, suggesting that this method can be employed to sequence EBOV genomes from ecologically or clinically derived samples...
August 2, 2018: Journal of Infectious Diseases
Kerry J Lavender, Brandi N Williamson, Greg Saturday, Cynthia Martellaro, Amanda Griffin, Kim J Hasenkrug, Heinz Feldmann, Joseph Prescott
Ebola virus (EBOV) and Marburg virus (MARV) outbreaks are highly lethal, and infection results in a hemorrhagic fever with complex etiology. These zoonotic viruses dysregulate the immune system to cause disease, in part by replicating within myeloid cells that would normally innately control viral infection and shape the adaptive immune response. We used triple knockout (TKO)-bone marrow, liver, thymus (BLT) humanized mice to recapitulate the early in vivo human immune response to filovirus infection. Disease severity in TKO-BLT mice was dissimilar between EBOV and MARV with greater severity observed during EBOV infection...
August 6, 2018: Journal of Infectious Diseases
Scott Martin, Abhilash I Chiramel, Marie Luisa Schmidt, Yu-Chi Chen, Nadia Whitt, Ari Watt, Eric C Dunham, Kyle Shifflett, Shelby Traeger, Anne Leske, Eugen Buehler, Cynthia Martellaro, Janine Brandt, Lisa Wendt, Andreas Müller, Stephanie Peitsch, Sonja M Best, Jürgen Stech, Stefan Finke, Angela Römer-Oberdörfer, Allison Groseth, Heinz Feldmann, Thomas Hoenen
BACKGROUND: The 2014-2016 Ebola virus (EBOV) outbreak in West Africa highlighted the need for improved therapeutic options against this virus. Approaches targeting host factors/pathways essential for the virus are advantageous because they can potentially target a wide range of viruses, including newly emerging ones and because the development of resistance is less likely than when targeting the virus directly. However, systematic approaches for screening host factors important for EBOV have been hampered by the necessity to work with this virus at biosafety level 4 (BSL4)...
August 7, 2018: Genome Medicine
Yang Liu, YuLan Sun, Wei Wu, AQian Li, XianDa Yang, Shuo Zhang, Chuan Li, QiuDong Su, ShaoJian Cai, DaPeng Sun, HaiYang Hu, Zhe Zhang, XiuXu Yang, Idrissa Kamara, Sheku Koroma, Gerald Bangura, Alie Tia, Abdul Kamara, Matt Lebby, Brima Kargbo, Jiandong Li, Shiwen Wang, XiaoPing Dong, YueLong Shu, WenBo Xu, George F Gao, GuiZhen Wu, DeXin Li, William J Liu, MiFang Liang
This study aimed to investigate the serological characteristics of Ebola virus (EBOV) infection during the late phase of the Ebola outbreak in Sierra Leone. In total, 877 blood samples from 694 suspected Ebola virus disease (EVD) cases assessed from March to December 2015, were analyzed via real-time reverse transcription polymerase chain reaction (RT-PCR) for viral RNA and enzyme-linked immunosorbent assay (ELISA) and Luminex to detect antibodies against EBOV. Viral load and EBOV-specific IgM/IgG titers displayed a declining trend during March to December 2015...
July 31, 2018: Virologica Sinica
Peter Halfmann, Lindsay Hill-Batorski, Yoshihiro Kawaoka
The inflammasome is part of the innate immune system that regulates the secretion of proinflammatory cytokines such as interleukin-1β (IL-1β). Ebola virus (EBOV) infection of monocytes and macrophages (primary target cells early during infection) leads to the production of proinflammatory cytokines; however, the mechanism behind the activation and release of these cytokines is not fully understood. Here, we demonstrate that EBOV infection leads to the activation of the NLRP3 inflammasome and the subsequent secretion of IL-1β and IL-18...
July 27, 2018: Journal of Infectious Diseases
Kazeem O Sulaiman, Temitope U Kolapo, Abdulmujeeb T Onawole, Ataul Islam, Rukayat O Adegoke, Suaibu O Badmus
Ebola virus (EBOV) is a lethal human pathogen with a risk of global spread of its zoonotic infections, and Ebolavirus Zaire specifically has the highest fatality rate amongst other species. There is a need for continuous effort towards having therapies, as a single licensed treatment to neutralize the EBOV is yet to come into reality. This present study virtually screened the MCULE database containing almost 36 million compounds against the structure of a Zaire Ebola viral protein (VP) 35 and a consensus scoring of both MCULE and CLCDDW docking programs remarked five compounds as potential hits...
July 30, 2018: Journal of Biomolecular Structure & Dynamics
John J Suschak, Kenneth Bagley, Charles J Shoemaker, Carolyn Six, Steven Kwilas, Lesley C Dupuy, Connie S Schmaljohn
In previous studies, we showed that deoxyribonucleic acid (DNA) vaccines expressing codon-optimized filovirus envelope glycoprotein genes protect mice and nonhuman primates from viral challenge when delivered by intramuscular (IM) electroporation (EP). To determine whether we could achieve equivalent immunogenicity and protective efficacy by a simplified delivery method, we generated DNA vaccine plasmids expressing genetic adjuvants to potentiate immune responses. We tested the Th1-inducing cytokine interleukin-12 and the granulocyte growth factor granulocyte-macrophage colony stimulating factor, both of which have demonstrated significant adjuvant effect when included in clinical DNA vaccine formulations...
July 19, 2018: Journal of Infectious Diseases
Ying Liu, Ling Ye, Fang Lin, Yasmine Gomaa, David Flyer, Ricardo Carrion, Jean L Patterson, Mark R Prausnitz, Gale Smith, Gregory Glenn, Hua Wu, Richard W Compans, Chinglai Yang
Development of a safe and efficacious filovirus vaccine is of high importance to public health. In this study, we compared immune responses induced by Ebola virus (EBOV) glycoprotein (GP) subunit vaccines via intradermal immunization with microneedle (MN) patches and the conventional intramuscular (IM) injection in mice, which showed that MN delivery of GP induced higher levels and longer lasting antibody responses against GP than IM injection. Further, we found that EBOV GP in formulation with a saponin-based adjuvant, Matrix-M, can be efficiently loaded onto MN patches...
July 25, 2018: Scientific Reports
Michelle E Olsen, Tessa N Cressey, Elke Mühlberger, John H Connor
Polyamines and hypusinated eIF5A have been implicated in the replication of diverse viruses, however, defining their roles in supporting virus replication is still under investigation. We have previously reported that Ebola virus (EBOV) requires polyamines and hypusinated eIF5A for replication. Using a replication deficient minigenome construct, we show that gene expression, in the absence of genome replication, requires hypusinated eIF5A. Additional experiments demonstrated the block in gene expression upon hypusine depletion was post-transcriptional, as minigenome reporter mRNA transcribed by the EBOV polymerase accumulated normally in the presence of drug treatment where protein did not...
July 25, 2018: Journal of Virology
Mariano Sanchez-Lockhart, Daniel S Reyes, Jeanette C Gonzalez, Karla Y Garcia, Erika C Villa, Bradley P Pfeffer, John C Trefry, Jeffrey R Kugelman, Margaret L Pitt, Gustavo F Palacios
Development of an effective vaccine became a worldwide priority after the devastating 2013-2016 Ebola disease outbreak. To qualitatively profile the humoral response against advanced filovirus vaccine candidates, we developed Domain Programmable Arrays (DPA), a systems serology platform to identify epitopes targeted after vaccination or filovirus infection. We optimized the assay using a panel of well-characterized monoclonal antibodies. After optimization, we utilized the system to longitudinally characterize the immunoglobulin (Ig) isotype-specific responses in non-human primates vaccinated with rVSV-ΔG-EBOV-glycoprotein (GP)...
July 24, 2018: Cell Reports
Jackson Emanuel, Julie Callison, Kimberly A Dowd, Theodore C Pierson, Heinz Feldmann, Andrea Marzi
Infection with Zika virus (ZIKV) is commonly mild in humans but has been associated with alarming negative health outcomes including Guillain-Barré syndrome in adults and microcephaly in fetuses. As such, developing a vaccine for ZIKV is a global public health priority. Recombinant vesicular stomatitis virus (VSV) expressing the Ebola virus (EBOV) glycoprotein (GP) has been successfully used as a vaccine platform in the past. In this study, two novel VSV-ZIKV vaccines were generated utilizing the favorable immune targeting of the existing VSV-EBOV vector...
July 23, 2018: Scientific Reports
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