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Kari A Dilley, Alexander A Voorhies, Priya Luthra, Vinita Puri, Timothy B Stockwell, Hernan Lorenzi, Christopher F Basler, Reed S Shabman
Ebola virus and Marburg virus are members of the Filovirdae family and causative agents of hemorrhagic fever with high fatality rates in humans. Filovirus virulence is partially attributed to the VP35 protein, a well-characterized inhibitor of the RIG-I-like receptor pathway that triggers the antiviral interferon (IFN) response. Prior work demonstrates the ability of VP35 to block potent RIG-I activators, such as Sendai virus (SeV), and this IFN-antagonist activity is directly correlated with its ability to bind RNA...
2017: PloS One
Thomas Brody, Amarendra S Yavatkar, Dong Sun Park, Alexander Kuzin, Jermaine Ross, Ward F Odenwald
BACKGROUND: Flavivirus and Filovirus infections are serious epidemic threats to human populations. Multi-genome comparative analysis of these evolving pathogens affords a view of their essential, conserved sequence elements as well as progressive evolutionary changes. While phylogenetic analysis has yielded important insights, the growing number of available genomic sequences makes comparisons between hundreds of viral strains challenging. We report here a new approach for the comparative analysis of these hemorrhagic fever viruses that can superimpose an unlimited number of one-on-one alignments to identify important features within genomes of interest...
June 16, 2017: PLoS Neglected Tropical Diseases
Amy J Schuh, Brian R Amman, Jonathan S Towner
While Reston and Lloviu viruses have never been associated with human disease, the other filoviruses cause outbreaks of hemorrhagic fever characterised by person-to-person transmission and high case fatality ratios. Cumulative evidence suggests that bats are the most likely reservoir hosts of the filoviruses. Ecological investigations following Marburg virus disease outbreaks associated with entry into caves inhabited by Rousettus aegyptiacus bats led to the identification of this bat species as the natural reservoir host of the marburgviruses...
March 2017: Microbiology Australia
Larissa Kolesnikova, Asuka Nanbo, Stephan Becker, Yoshihiro Kawaoka
This chapter reviews our current knowledge about the spatiotemporal assembly of filoviral particles. We will follow particles from nucleocapsid entry into the cytoplasm until the nucleocapsids are enveloped at the plasma membrane. We will also highlight the currently open scientific questions surrounding filovirus assembly.
June 11, 2017: Current Topics in Microbiology and Immunology
R A Davey, O Shtanko, M Anantpadma, Y Sakurai, K Chandran, W Maury
Filovirus entry into cells is complex, perhaps as complex as any viral entry mechanism identified to date. However, over the past 10 years, the important events required for filoviruses to enter into the endosomal compartment and fuse with vesicular membranes have been elucidated (Fig. 1). Here, we highlight the important steps that are required for productive entry of filoviruses into mammalian cells.
June 11, 2017: Current Topics in Microbiology and Immunology
Jim Duehr, Teddy John Wohlbold, Lisa Oestereich, Veronika Chromikova, Fatima Amanat, Madhusudan Rajendran, Sergio Gomez-Medina, Ignacio Mena, Benjamin R TenOever, Adolfo García-Sastre, Christopher F Basler, Cesar Munoz-Fontela, Florian Krammer
Out of an estimated 31,100 cases since its discovery in 1976, ebolaviruses have caused approximately 13,000 deaths. The vast majority (∼11,000) of these occurred during the 2013-2016 West African epidemic. Three out of five species in the genus are known to cause Ebola Virus Disease in humans. Several monoclonal antibodies against the ebolavirus glycoprotein are currently in development as therapeutics. However, there is still a paucity of monoclonal antibodies that can cross-react between the glycoproteins of different ebolavirus species and the mechanism of these monoclonal antibody therapeutics are still not understood in detail...
June 7, 2017: Journal of Virology
Nisha Bhattarai, Jeevan B Gc, Bernard S Gerstman, Robert V Stahelin, Prem P Chapagain
Filovirus infections cause hemorrhagic fever in humans and non-human primates that often results in high fatality rates. The Marburg virus is a lipid-enveloped virus from the Filoviridae family and is closely related to the Ebola virus. The viral matrix layer underneath the lipid envelope is formed by the matrix protein VP40 (VP40), which is also involved in other functions during the viral life-cycle. As in the Ebola virus VP40 (eVP40), the recently determined X-ray crystal structure of the Marburg virus VP40 (mVP40) features loops containing cationic residues that form a lipid binding basic patch...
April 26, 2017: RSC Advances
Robert W Cross, Thomas G Ksiazek
Immunologic assays such as ELISA allow detection of either virus antigens or the host's immune response to antigens associated with prior infections and offer a powerful means to approach understanding the epidemiology and epizootiology of these agents. However, the success of these assays is highly dependent on the production of high-quality materials both to establish the assays (i.e., antigen target for antibody) and to serve as controls for establishing assay parameters and sensitivity. Here we describe methods for preparing ebolavirus antigens suitable for use as either reagents or controls in a variety of ELISA formats...
2017: Methods in Molecular Biology
Wakako Furuyama, Hiroko Miyamoto, Reiko Yoshida, Ayato Takada
Serological methods such as the enzyme-linked immunosorbent assay (ELISA) and virus neutralization test are fundamental tools used in diagnosis, seroepidemiological studies of filovirus transmission/prevalence, and the evaluation of vaccine immunogenicity and potential therapeutic antibodies. Filoviruses have a single transmembrane glycoprotein (GP), which is the only known target of neutralizing antibodies. Here we describe serological methods to quantify filovirus GP-specific antibodies.
2017: Methods in Molecular Biology
Darryl Falzarano
Assessment of small molecule compounds against filoviruses, such as Ebola virus, has identified numerous compounds that appear to have antiviral activity and should presumably be further investigated in animal efficacy trials. However, despite the many compounds that are purported to have good antiviral activity in in vitro studies, there are few instances where any efficacy has been reported in nonhuman primate models. Many of the high-throughput screening assays use reporter systems that only recapitulate a portion of the virus life cycle, while other assays only assess antiviral activity at relatively early time points...
2017: Methods in Molecular Biology
Gordian Schudt, Olga Dolnik, Stephan Becker
Observation of molecular processes inside living cells is fundamental to a deeper understanding of virus-host interactions in filoviral-infected cells. These observations can provide spatiotemporal insights into protein synthesis, protein-protein interaction dynamics, and transport processes of these highly pathogenic viruses. Thus, live-cell imaging provides the possibility for antiviral screening in real time and gives mechanistic insights into understanding filovirus assembly steps that are dependent on cellular factors, which then represent potential targets against this highly fatal disease...
2017: Methods in Molecular Biology
Allison Groseth
Reverse genetics systems encompass a wide array of tools aimed at recapitulating some or all of the virus life cycle. In their most complete form, full-length clone systems allow us to use plasmid-encoded versions of the ribonucleoprotein (RNP) components to initiate the transcription and replication of a plasmid-encoded version of the complete viral genome, thereby initiating the complete virus life cycle and resulting in infectious virus. As such this approach is ideal for the generation of tailor-made recombinant filoviruses, which can be used to study virus biology...
2017: Methods in Molecular Biology
Claire Marie Filone, David Miller, Victoria Wahl-Jensen
The 50% tissue culture infectious dose (TCID50) endpoint dilution assay is one of the gold standard methods for measuring filovirus infectivity. We have increased virology microtitration assay throughput at biosafety level (BSL)-4 by implementing automated liquid handling and semi-automated assay endpoint readout. Utilization of automated liquid handling for cell plating and virus dilution along with optimization of the assay endpoint readout, using a luminescent-based cell viability assay and an automated plate reader, has improved workflow efficiency, reduced operator burden and assay time, decreased assay variability, and increased data return...
2017: Methods in Molecular Biology
Priya Luthra, Christopher F Basler
Innate immunity is the first line of defense against virus infections and is marked by production of type I interferons (IFN), a family of cytokines that includes IFN-β and several IFN-αs. For the filoviruses and many other RNA viruses that replicate in the cytoplasm, the RIG-I-like pattern recognition receptors (RLRs) are potential triggers of IFN production. To counteract such innate antiviral responses, many viruses encode proteins that antagonize RLR signaling. Ebola virus (EBOV) and other filoviruses produce VP35 proteins that block IFN induction via RLR signaling...
2017: Methods in Molecular Biology
Patrick L Sinn, Jeremy E Coffin, Natarajan Ayithan, Kathleen H Holt, Wendy Maury
Pseudotyping lentivirus-based vectors is a strategy used to study conferred vector tropism and mechanisms of envelope glycoprotein function. Lentiviruses and filoviruses both assemble at the plasma membrane and have homotrimeric structural envelope glycoproteins that mediate both receptor binding and fusion. Such similarities help foster efficient pseudotyping. Importantly, filovirus glycoprotein pseudotyping of lentiviral vectors allows investigators to study virus entry at substantially less restrictive levels of biosafety containment than that required for wild-type filovirus work (biosafety level-2 vs...
2017: Methods in Molecular Biology
Rachel B Brouillette, Wendy Maury
Members of the family Filoviridae are filamentous, enveloped, and nonsegmented negative-stranded RNA viruses that can cause severe hemorrhagic disease in humans and nonhuman primates with high mortality rates. Current efforts to analyze the structure and biology of these viruses as well as the development of antivirals have been hindered by the necessity of biosafety level 4 containment (BSL4). Here, we outline how to produce and work with Ebola virus glycoprotein bearing vesicular stomatitis virus (VSV) pseudovirions...
2017: Methods in Molecular Biology
Hans Dieter Klenk, Werner Slenczka
Since the discovery of Marburg virus 50 years ago, filoviruses have reemerged in the human population more than 40 times. Already the first episode was as dramatic as most of the subsequent ones, but none of them was as devastating as the West-African Ebola virus outbreak in 2013-2015. Although progress toward a better understanding of the viruses is impressive, there is clearly a need to improve and strengthen the measures to detect and control these deadly infections.
2017: Methods in Molecular Biology
Baocheng Liu, Shishang Dong, Guobang Li, Wenming Wang, Xiang Liu, Yantong Wang, Cheng Yang, Zihe Rao, Yu Guo
Marburg virus (MARV) encodes a nucleoprotein (NP) to encapsidate its genome by oligomerization and form ribonucleoprotein complex (RNP). According to previous investigation on nonsegmented negative-sense RNA viruses (nsNSV), the newly synthesized NPs must be prevented from indiscriminately binding to noncognate RNAs. During the viral RNA synthesis process, the RNP undergo a transition from RNA-bound form to template-free form, to open access for the interaction between viral polymerase with RNA template. In filovirus, this transition is regulated by the VP35 and other viral components...
May 31, 2017: Journal of Virology
Christopher F Basler
The clinical syndrome referred to as viral hemorrhagic fever (VHF) can be caused by several different families of RNA viruses, including select members of the arenaviruses, bunyaviruses, filoviruses, and flaviviruses. VHF is characterized by malaise, fever, vascular permeability, decreased plasma volume, coagulation abnormalities, and varying degrees of hemorrhage. Study of the filovirus Ebola virus has demonstrated a critical role for suppression of innate antiviral defenses in viral pathogenesis. Additionally, antigen-presenting cells are targets of productive infection and immune dysregulation...
May 29, 2017: Seminars in Immunopathology
Andrea Kroeker, Shihua He, Marc-Antoine de La Vega, Gary Wong, Carissa Embury-Hyatt, Xiangguo Qiu
Sudan virus (SUDV) outbreaks in Africa are highly lethal; however, the development and testing of novel antivirals and vaccines for this virus has been limited by a lack of suitable animal models. Non-human primates (NHP) remain the gold standard for modeling filovirus disease, but they are not conducive to screening large numbers of experimental compounds and should only be used to test the most promising candidates. Therefore, other smaller animal models are a valuable asset. We have recently developed a guinea-pig adapted SUDV virus that is lethal in guinea pigs...
May 8, 2017: Oncotarget
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