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Flavivirus assembly

Edson R A Oliveira, Ronaldo Mohana-Borges, Ricardo B de Alencastro, Bruno A C Horta
Flaviviruses, such as dengue and zika viruses, are etiologic agents transmitted to humans mainly by arthropods and are of great epidemiological interest. The flavivirus capsid protein is a structural element required for the viral nucleocapsid assembly that presents the classical function of sheltering the viral genome. After decades of research, many reports have shown its different functionalities and influence over cell normal functioning. The subcellular distribution of this protein, which involves accumulation around lipid droplets and nuclear localization, also corroborates with its multi-functional characteristic...
October 14, 2016: Virus Research
Miguel A Martín-Acebes, Ángela Vázquez-Calvo, Juan-Carlos Saiz
Flaviviruses are emerging arthropod-borne pathogens that cause life-threatening diseases such as yellow fever, dengue, West Nile encephalitis, tick-borne encephalitis, Kyasanur Forest disease, tick-borne encephalitis, or Zika disease. This viral genus groups >50 viral species of small enveloped plus strand RNA virus that are phylogenetically closely related to hepatitis C virus. Importantly, the flavivirus life cycle is intimately associated to host cell lipids. Along this line, flaviviruses rearrange intracellular membranes from the endoplasmic-reticulum of the infected cells to develop adequate platforms for viral replication and particle biogenesis...
October 1, 2016: Progress in Lipid Research
Delia Tarantino, Rolando Cannalire, Eloise Mastrangelo, Romina Croci, Gilles Querat, Maria Letizia Barreca, Martino Bolognesi, Giuseppe Manfroni, Violetta Cecchetti, Mario Milani
RNA dependent RNA polymerases (RdRp) are essential enzymes for flavivirus replication. Starting from an in silico docking analysis we identified a pyridobenzothiazole compound, HeE1-2Tyr, able to inhibit West Nile and Dengue RdRps activity in vitro, which proved effective against different flaviviruses in cell culture. Crystallographic data show that HeE1-2Tyr binds between the fingers domain and the priming loop of Dengue virus RdRp (Site 1). Conversely, enzyme kinetics, binding studies and mutational analyses suggest that, during the catalytic cycle and assembly of the RdRp-RNA complex, HeE1-2Tyr might be hosted in a distinct binding site (Site 2)...
October 2016: Antiviral Research
Keisuke Tabata, Masaru Arimoto, Masashi Arakawa, Atsuki Nara, Kazunobu Saito, Hiroko Omori, Arisa Arai, Tomohiro Ishikawa, Eiji Konishi, Ryosuke Suzuki, Yoshiharu Matsuura, Eiji Morita
Flavivirus infection induces endoplasmic reticulum (ER) membrane rearrangements to generate a compartment for replication of the viral genome and assembly of viral particles. Using quantitative mass spectrometry, we identified several ESCRT (endosomal sorting complex required for transport) proteins that are recruited to sites of virus replication on the ER. Systematic small interfering RNA (siRNA) screening revealed that release of both dengue virus and Japanese encephalitis virus was dramatically decreased by single depletion of TSG101 or co-depletion of specific combinations of ESCRT-III proteins, resulting in ≥1,000-fold titer reductions...
August 30, 2016: Cell Reports
Amber M Paul, Zhen Fan, Sudarson S Sinha, Yongliang Shi, Linda Le, Fengwei Bai, Paresh C Ray
Dengue virus (DENV) and West Nile virus (WNV) are two well-documented mosquito-borne flaviviruses that cause significant health problems worldwide. Driven by this need, we have developed a bio-conjugated gold nanoparticle (AuNP)-based surface enhanced Raman spectroscopy (SERS) probe for the detection of both DENV and WNV. Reported data demonstrate anti-flavivirus 4G2 antibody conjugated gold nanoparticle (GNP) SERS probe can be used as a Raman fingerprint for the ultrasensitive detection of DENV and WNV selectively...
October 15, 2015: Journal of Physical Chemistry. C, Nanomaterials and Interfaces
Sue E Crawford, Ulrich Desselberger
Recent evidence has demonstrated that a variety of pathogens target cellular lipid metabolism for their replication. Lipid droplets are a major contributor to lipid homeostasis and contain neutral fats but are also recognized as dynamic organelles involved in signal transduction, membrane trafficking and modulation of immune and inflammatory responses. Rotaviruses co-opt lipid droplets for their replication. Rotavirus viroplasms, sites of viral RNA replication and immature particle assembly, form complexes with cellular lipid droplets early in infection...
August 2016: Current Opinion in Virology
Travis J Taylor, Fernando Diaz, Robert C Colgrove, Kristen A Bernard, Neal A DeLuca, Sean P J Whelan, David M Knipe
West Nile virus (WNV) is a flavivirus that swept rapidly across North America in 1999, declined in prevalence, and then resurged in 2012. To date, no vaccine is available to prevent infection in the human population. Herpes simplex virus (HSV) replication-defective vaccine vectors induce a durable immunity characterized by strong antibody and CD8(+) T cell responses even in HSV-immune animals. In this study, a WNV protein expression cassette was optimized for virus-like particle (VLP) production in transfection studies, and the cassette was recombined into an HSV-1 d106-WNV virus vector, which produced extracellular VLPs, as confirmed by immunoelectron microscopy...
September 2016: Virology
Victor Satler Pylro, Francislon Silva Oliveira, Daniel Kumazawa Morais, Sara Cuadros-Orellana, Fabiano Sviatopolk-Mirsky Pais, Julliane Dutra Medeiros, Juliana Assis Geraldo, Jack Gilbert, Angela Cristina Volpini, Gabriel Rocha Fernandes
BACKGROUND: In early 2015, a ZIKA Virus (ZIKV) infection outbreak was recognized in northeast Brazil, where concerns over its possible links with infant microcephaly have been discussed. Providing a causal link between ZIKV infection and birth defects is still a challenge. MicroRNAs (miRNAs) are small noncoding RNAs (sncRNAs) that regulate post-transcriptional gene expression by translational repression, and play important roles in viral pathogenesis and brain development. The potential for flavivirus-mediated miRNA signalling dysfunction in brain-tissue development provides a compelling hypothesis to test the perceived link between ZIKV and microcephaly...
June 2016: PLoS Neglected Tropical Diseases
Janja Blazevic, Harald Rouha, Victoria Bradt, Franz X Heinz, Karin Stiasny
UNLABELLED: The structural proteins of flaviviruses carry a unique set of transmembrane domains (TMDs) at their C termini that are derived from the mode of viral polyprotein processing. They function as internal signal and stop-transfer sequences during protein translation, but possible additional roles in protein interactions required during assembly and maturation of viral particles are ill defined. To shed light on the role of TMDs in these processes, we engineered a set of tick-borne encephalitis virus mutants in which these structural elements were replaced in different combinations by the homologous sequences of a distantly related flavivirus (Japanese encephalitis virus)...
July 15, 2016: Journal of Virology
Xiao-Dan Li, Cheng-Lin Deng, Han-Qing Ye, Hong-Lei Zhang, Qiu-Yan Zhang, Dong-Dong Chen, Pan-Tao Zhang, Pei-Yong Shi, Zhi-Ming Yuan, Bo Zhang
UNLABELLED: Flavivirus nonstructural protein 2B (NS2B) is a transmembrane protein that functions as a cofactor for viral NS3 protease. The cytoplasmic region (amino acids 51 to 95) alone of NS2B is sufficient for NS3 protease activity, whereas the role of transmembrane domains (TMDs) remains obscure. Here, we demonstrate for the first time that flavivirus NS2B plays a critical role in virion assembly. Using Japanese encephalitis virus (JEV) as a model, we performed a systematic mutagenesis at the flavivirus conserved residues within the TMDs of NS2B...
June 15, 2016: Journal of Virology
Leopoldo G Gebhard, Néstor G Iglesias, Laura A Byk, Claudia V Filomatori, Federico A De Maio, Andrea V Gamarnik
UNLABELLED: Dengue virus is currently the most important insect-borne viral human pathogen. Viral nonstructural protein 3 (NS3) is a key component of the viral replication machinery that performs multiple functions during viral replication and participates in antiviral evasion. Using dengue virus infectious clones and reporter systems to dissect each step of the viral life cycle, we examined the requirements of different domains of NS3 on viral particle assembly. A thorough site-directed mutagenesis study based on solvent-accessible surface areas of NS3 revealed that, in addition to being essential for RNA replication, different domains of dengue virus NS3 are critically required for production of infectious viral particles...
June 1, 2016: Journal of Virology
Miguel A Martín-Acebes, Ana-Belén Blázquez, Rodrigo Cañas-Arranz, Ángela Vázquez-Calvo, Teresa Merino-Ramos, Estela Escribano-Romero, Francisco Sobrino, Juan-Carlos Saiz
Usutu virus (USUV) is a mosquito-borne flavivirus whose circulation had been confined to Africa since it was first detected in 1959. However, in the last decade USUV has emerged in Europe causing episodes of avian mortality and sporadic severe neuroinvasive infections in humans. Remarkably, adult laboratory mice exhibit limited susceptibility to USUV infection, which has impaired the analysis of the immune responses, thus complicating the evaluation of virus-host interactions and of vaccine candidates against this pathogen...
April 19, 2016: Vaccine
Valerie J Klema, Mengyi Ye, Aditya Hindupur, Tadahisa Teramoto, Keerthi Gottipati, Radhakrishnan Padmanabhan, Kyung H Choi
Flavivirus nonstructural protein 5 (NS5) consists of methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRp) domains, which catalyze 5'-RNA capping/methylation and RNA synthesis, respectively, during viral genome replication. Although the crystal structure of flavivirus NS5 is known, no data about the quaternary organization of the functional enzyme are available. We report the crystal structure of dengue virus full-length NS5, where eight molecules of NS5 are arranged as four independent dimers in the crystallographic asymmetric unit...
February 2016: PLoS Pathogens
Jeffrey M Grabowski, Rushika Perera, Ali M Roumani, Victoria E Hedrick, Halina D Inerowicz, Catherine A Hill, Richard J Kuhn
BACKGROUND: Ticks (Family Ixodidae) transmit a variety of disease causing agents to humans and animals. The tick-borne flaviviruses (TBFs; family Flaviviridae) are a complex of viruses, many of which cause encephalitis and hemorrhagic fever, and represent global threats to human health and biosecurity. Pathogenesis has been well studied in human and animal disease models. Equivalent analyses of tick-flavivirus interactions are limited and represent an area of study that could reveal novel approaches for TBF control...
February 2016: PLoS Neglected Tropical Diseases
Mélissanne de Wispelaere, Cécile Khou, Marie-Pascale Frenkiel, Philippe Desprès, Nathalie Pardigon
UNLABELLED: Japanese encephalitis virus (JEV) membrane (M) protein plays important structural roles in the processes of fusion and maturation of progeny virus during cellular infection. The M protein is anchored in the viral membrane, and its ectodomain is composed of a flexible N-terminal loop and a perimembrane helix. In this study, we performed site-directed mutagenesis on residue 36 of JEV M protein and showed that the resulting mutation had little or no effect on the entry process but greatly affected virus assembly in mammalian cells...
December 9, 2015: Journal of Virology
E N Gallichotte, D G Widman, B L Yount, W M Wahala, A Durbin, S Whitehead, C A Sariol, J E Crowe, A M de Silva, R S Baric
UNLABELLED: Dengue virus serotype 2 (DENV2) is widespread and responsible for severe epidemics. While primary DENV2 infections stimulate serotype-specific protective responses, a leading vaccine failed to induce a similar protective response. Using human monoclonal antibodies (hMAbs) isolated from dengue cases and structure-guided design of a chimeric DENV, here we describe the major site on the DENV2 envelope (E) protein targeted by neutralizing antibodies. DENV2-specific neutralizing hMAb 2D22 binds to a quaternary structure epitope...
October 13, 2015: MBio
Kar Yue Foo, Hui-Yee Chee
Flaviviruses are potentially human pathogens that cause major epidemics worldwide. Flavivirus interacts with host cell factors to form a favourable virus replication site. Cell cytoskeletons have been observed to have close contact with flaviviruses, which expands the understanding of cytoskeleton functions during virus replication, although many detailed mechanisms are still unclear. The interactions between the virus and host cytoskeletons such as actin filaments, microtubules, and intermediate filaments have provided insight into molecular alterations during the virus infection, such as viral entry, in-cell transport, scaffold assembly, and egress...
2015: BioMed Research International
Valerie J Klema, Radhakrishnan Padmanabhan, Kyung H Choi
Genome replication in flavivirus requires (-) strand RNA synthesis, (+) strand RNA synthesis, and 51-RNA capping and methylation. To carry out viral genome replication, flavivirus assembles a replication complex, consisting of both viral and host proteins, on the cytoplasmic side of the endoplasmic reticulum (ER) membrane. Two major components of the replication complex are the viral non-structural (NS) proteins NS3 and NS5. Together they possess all the enzymatic activities required for genome replication, yet how these activities are coordinated during genome replication is not clear...
August 2015: Viruses
Laura A VanBlargan, Kaitlin A Davis, Kimberly A Dowd, David L Akey, Janet L Smith, Theodore C Pierson
UNLABELLED: The molecular mechanisms that define the specificity of flavivirus RNA encapsulation are poorly understood. Virions composed of the structural proteins of one flavivirus and the genomic RNA of a heterologous strain can be assembled and have been developed as live attenuated vaccine candidates for several flaviviruses. In this study, we discovered that not all combinations of flavivirus components are possible. While a West Nile virus (WNV) subgenomic RNA could readily be packaged by structural proteins of the DENV2 strain 16681, production of infectious virions with DENV2 strain New Guinea C (NGC) structural proteins was not possible, despite the very high amino acid identity between these viruses...
August 2015: Journal of Virology
Dahai Luo, Subhash G Vasudevan, Julien Lescar
The flavivirus NS3 protein is associated with the endoplasmic reticulum membrane via its close interaction with the central hydrophilic region of the NS2B integral membrane protein. The multiple roles played by the NS2B-NS3 protein in the virus life cycle makes it an attractive target for antiviral drug discovery. The N-terminal region of NS3 and its cofactor NS2B constitute the protease that cleaves the viral polyprotein. The NS3 C-terminal domain possesses RNA helicase, nucleoside and RNA triphosphatase activities and is involved both in viral RNA replication and virus particle formation...
June 2015: Antiviral Research
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