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Dengue ns2a

Sneha Singh, M G Anupriya, Easwaran Sreekumar
The role of genetic differences among dengue virus (DENV) in causing increased microvascular permeability is less explored. In the present study, we compared two closely related DENV serotype-2 strains of Cosmopolitan genotype for their in vitro infectivity phenotype and ability to induce trans-endothelial leakage. We found that these laboratory strains differed significantly in infecting human microvascular endothelial cells (HMEC-1) and hepatocytes (Huh7), two major target cells of DENV in in vivo infections...
April 27, 2017: Infection, Genetics and Evolution
Abbas El Sahili, Julien Lescar
The World Health Organization estimates that the yearly number of dengue cases averages 390 million. This mosquito-borne virus disease is endemic in over 100 countries and will probably continue spreading, given the observed trend in global warming. So far, there is no antiviral drug available against dengue, but a vaccine has been recently marketed. Dengue virus also serves as a prototype for the study of other pathogenic flaviviruses that are emerging, like West Nile virus and Zika virus. Upon viral entry into the host cell and fusion of the viral lipid membrane with the endosomal membrane, the viral RNA is released and expressed as a polyprotein, that is then matured into three structural and seven non-structural (NS) proteins...
April 24, 2017: Viruses
Ren-Huang Wu, Ming-Han Tsai, Kuen-Nan Tsai, Jia Ni Tian, Jian-Sung Wu, Su-Ying Wu, Jyh-Haur Chern, Chun-Hong Chen, Andrew Yueh
The NS2A protein of Dengue virus (DENV) has eight predicted transmembrane segments (pTMS1-8) and participates in RNA replication, virion assembly, and host antiviral response. However, the roles of specific amino acid residues within the pTMS regions of NS2A during the viral life cycle are not clear. Here, we explored the function of DENV NS2A by introducing a series of alanine substitutions into the N-terminal half (pTMS1-4) of the protein in the context of a DENV infectious clone or subgenomic replicon. Six NS2A mutants (NM5, 7, 9, and 17-19) around pTMS1-2 displayed a novel phenotype showing a >1000-fold reduction in virus yield, an absence of plaque formation despite wild-type-like replicon activity, and infectious virus-like particle yields...
April 5, 2017: Journal of Virology
Jonas N Conde, Emiliana M Silva, Angela S Barbosa, Ronaldo Mohana-Borges
The incidence of flavivirus infections has increased dramatically in recent decades in tropical and sub-tropical climates worldwide, affecting hundreds of millions of people each year. The Flaviviridae family includes dengue, West Nile, Zika, Japanese encephalitis, and yellow fever viruses that are typically transmitted by mosquitoes or ticks, and cause a wide range of symptoms, such as fever, shock, meningitis, paralysis, birth defects, and death. The flavivirus genome is composed of a single positive-sense RNA molecule encoding a single viral polyprotein...
2017: Frontiers in Microbiology
Jasper Fuk-Woo Chan, Cyril Chik-Yan Yip, Kah-Meng Tee, Zheng Zhu, Jessica Oi-Ling Tsang, Kenn Ka-Heng Chik, Terance Gi-Wai Tsang, Chris Chung-Sing Chan, Vincent Kwok-Man Poon, Siddharth Sridhar, Feifei Yin, Ivan Fan-Ngai Hung, Sandy Ka-Yee Chau, Anna Jinxia Zhang, Kwok-Hung Chan, Kwok-Yung Yuen
OBJECTIVE AND METHOD: We developed and evaluated five novel real-time RT-PCR assays targeting conserved regions in the 5'-untranslated region (5'-UTR), envelope (E'), non-structural protein 2A (NS2A), NS5 and 3'-UTR of the ZIKV genome. RESULTS: The ZIKV-5'-UTR assay exhibited the lowest in vitro limit of detection (5-10 RNA copies/reaction and 3.0 × 10(-1) plaque-forming units/ml). Compared to the modified version of a widely adopted RT-PCR assay targeting the ZIKV-E gene, the ZIKV-5'-UTR assay showed better sensitivity in human clinical specimens, and representative mouse specimens, including many organs which are known to be involved in human ZIKV infection but difficult to obtain in clinical settings...
February 18, 2017: Tropical Medicine & International Health: TM & IH
Patricia Bautista-Carbajal, Ruben Soto-Acosta, Antonio H Angel-Ambrocio, Margot Cervantes-Salazar, Circe I Loranca-Vega, Mayra Herrera-Martínez, Rosa M Del Angel
Dengue virus (DENV) replicative cycle occurs in the endoplasmic reticulum where calcium ions play an important role in cell signaling. Calmodulin (CaM) is the primary sensor of intracellular Ca(2+) levels in eukaryotic cells. In this paper, the effect of the calmodulin antagonist W-7 in DENV infection in Huh-7 cells was evaluated. W7 inhibited viral yield, NS1 secretion and viral RNA and protein synthesis. Moreover, luciferase activity, encoded by a DENV replicon, was also reduced. A decrease in the replicative complexes formation was clearly observed in W7 treated cells...
January 15, 2017: Virology
Sean Ekins, John Liebler, Bruno J Neves, Warren G Lewis, Megan Coffee, Rachelle Bienstock, Christopher Southan, Carolina H Andrade
The Zika virus (ZIKV) is a flavivirus of the family Flaviviridae, which is similar to dengue virus, yellow fever and West Nile virus. Recent outbreaks in South America, Latin America, the Caribbean and in particular Brazil have led to concern for the spread of the disease and potential to cause Guillain-Barré syndrome and microcephaly. Although ZIKV has been known of for over 60 years there is very little in the way of knowledge of the virus with few publications and no crystal structures. No antivirals have been tested against it either in vitro or in vivo...
2016: F1000Research
Daniela Weiskopf, Michael A Angelo, Alba Grifoni, Patrick H O'Rourke, John Sidney, Sinu Paul, Aruna D De Silva, Elizabeth Phillips, Simon Mallal, Sunil Premawansa, Gayani Premawansa, Ananda Wijewickrama, Bjoern Peters, Alessandro Sette
BACKGROUND: Each year dengue virus (DENV) infects 400 million human but causes symptomatic disease in only a subset of patients, suggesting that host genetic factors may play a role. HLA molecules that restrict T-cell responses are one of the most polymorphic host factors in humans. METHODS: Here we map HLA DRB1-restricted DENV-specific epitopes in individuals previously exposed to DENV, to identify the breadth and specificity of CD4(+) T-cell responses. To investigate whether HLA-specific variations in the magnitude of response might predict associations between dengue outcomes and HLA-DRB1 alleles, we assembled samples from hospitalized patients with known severity of disease...
October 1, 2016: Journal of Infectious Diseases
Bryan D Cox, Richard A Stanton, Raymond F Schinazi
BACKGROUND: Zika virus is an emerging crisis as infection is implicated in severe neurological disorders-Guillain-Barré syndrome and fetal microcephaly. There are currently no treatment options available for Zika virus infection. This virus is part of the flavivirus genus and closely related to Dengue Fever Virus, West Nile Virus, and Japanese Encephalitis Virus. Like other flaviviruses, the Zika virus genome encodes three structural proteins (capsid, precursor membrane, and envelope) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5)...
August 2015: Antiviral Chemistry & Chemotherapy
Vaishali P Waman, Sunitha Manjari Kasibhatla, Mohan M Kale, Urmila Kulkarni-Kale
The spread of dengue disease has become a global public health concern. Dengue is caused by dengue virus, which is a mosquito-borne arbovirus of the genus Flavivirus, family Flaviviridae. There are four dengue virus serotypes (1-4), each of which is known to trigger mild to severe disease. Dengue virus serotype 4 (DENV-4) has four genotypes and is increasingly being reported to be re-emerging in various parts of the world. Therefore, the population structure and factors shaping the evolution of DENV-4 strains across the world were studied using genome-based population genetic, phylogenetic and selection pressure analysis methods...
August 2016: Archives of Virology
Siti Nor Khadijah Addis, Eva Lee, Jayaram Bettadapura, Mario Lobigs
BACKGROUND: Our understanding of the proteolytic processing events at the NS1-2A junction in the flavivirus polyprotein has not markedly progressed since the early work conducted on dengue virus (DENV). This work identified an octapeptide sequence located immediately upstream of the cleavage site thought to be important in substrate recognition by an as yet unknown, endoplasmic reticulum-resident host protease. Of the eight amino acid recognition sequence, the highly conserved residues at positions P1, P3, P5, P7 and P8 (with respect to N-terminus of NS2A) are particularly sensitive to amino acid substitutions in terms of DENV NS1-NS2A cleavage efficiency; however, the role of the octapeptide in efficient NS1 and NS2A production of other flaviviruses has not been experimentally addressed...
2015: Virology Journal
Nadine A Dalrymple, Velasco Cimica, Erich R Mackow
UNLABELLED: Dengue virus (DENV) replication is inhibited by the prior addition of type I interferon or by RIG-I agonists that elicit RIG-I/MAVS/TBK1/IRF3-dependent protective responses. DENV infection of primary human endothelial cells (ECs) results in a rapid increase in viral titer, which suggests that DENV inhibits replication-restrictive RIG-I/interferon beta (IFN-β) induction pathways within ECs. Our findings demonstrate that DENV serotype 4 (DENV4) nonstructural (NS) proteins NS2A and NS4B inhibited RIG-I-, MDA5-, MAVS-, and TBK1/IKKε-directed IFN-β transcription (>80%) but failed to inhibit IFN-β induction directed by STING or constitutively active IRF3-5D...
May 12, 2015: MBio
Jin-Kyoung Kim, Jeong-Min Kim, Byung-Hak Song, Sang-Im Yun, Gil-Nam Yun, Sung-June Byun, Young-Min Lee
Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is closely related to West Nile (WN), yellow fever (YF), and dengue (DEN) viruses. Its plus-strand genomic RNA carries a single open reading frame encoding a polyprotein that is cleaved into three structural (C, prM/M, and E) and at least seven nonstructural (NS1/NS1', NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins, based on previous work with WNV, YFV, and DENV. Here, we aimed to profile experimentally all the viral proteins found in JEV-infected cells...
2015: PloS One
Hapuarachchige Chanditha Hapuarachchi, Rachel Choon Rong Chua, Yuan Shi, Tun Lin Thein, Linda Kay Lee, Kim Sung Lee, David Chien Lye, Lee Ching Ng, Yee Sin Leo
The exact mechanisms of interplay between host and viral factors leading to severe dengue are yet to be fully understood. Even though previous studies have implicated specific genetic differences of Dengue virus (DENV) in clinical severity and virus attenuation, similar studies with large-scale, whole genome screening of monophyletic virus populations are limited. Therefore, in the present study, we compared 89 whole genomes of DENV-2 cosmopolitan clade III isolates obtained from patients diagnosed with dengue fever (DF, n = 58), dengue hemorrhagic fever (DHF, n = 30) and dengue shock syndrome (DSS, n = 1) in Singapore between July 2010 and January 2013, in order to determine the correlation of observed viral genetic differences with clinical outcomes...
2015: PloS One
Ren-Huang Wu, Ming-Han Tsai, Day-Yu Chao, Andrew Yueh
UNLABELLED: The NS2A protein of dengue virus (DENV) has eight predicted transmembrane segments (pTMSs; pTMS1 to pTMS8). NS2A has been shown to participate in RNA replication, virion assembly, and the host antiviral response. However, the role of the amino acid residues within the pTMS regions of NS2A during the virus life cycle is poorly understood. In the study described here, we explored the function of DENV NS2A by introducing a series of double or triple alanine substitutions into the C-terminal half (pTMS4 to pTMS8) of NS2A in the context of a DENV infectious clone or subgenomic replicon...
April 2015: Journal of Virology
Jorge Andrés Castillo Ramirez, Silvio Urcuqui-Inchima
The arthropod-borne diseases caused by dengue virus (DENV) are a major and emerging problem of public health worldwide. Infection with DENV causes a series of clinical manifestations ranging from mild flu syndrome to severe diseases that include hemorrhage and shock. It has been demonstrated that the innate immune response plays a key role in DENV pathogenesis. However, in recent years, it was shown that DENV evades the innate immune response by blocking type I interferon (IFN-I). It has been demonstrated that DENV can inhibit both the production and the signaling of IFN-I...
June 2015: Journal of Interferon & Cytokine Research
Jing Zou, Xuping Xie, Qing-Yin Wang, Hongping Dong, Michelle Yueqi Lee, Congbao Kang, Zhiming Yuan, Pei-Yong Shi
UNLABELLED: Flavivirus replication is mediated by a membrane-associated replication complex where viral membrane proteins NS2A, NS2B, NS4A, and NS4B serve as the scaffold for the replication complex formation. Here, we used dengue virus serotype 2 (DENV-2) as a model to characterize viral NS4A-NS4B interaction. NS4A interacts with NS4B in virus-infected cells and in cells transiently expressing NS4A and NS4B in the absence of other viral proteins. Recombinant NS4A and NS4B proteins directly bind to each other with an estimated Kd (dissociation constant) of 50 nM...
April 2015: Journal of Virology
Zhi-Liang Duan, Hui-Fang Liu, Xi Huang, Si-Na Wang, Jin-Lin Yang, Xin-Yu Chen, De-Zhou Li, Xiao-Zhi Zhong, Bo-Kun Chen, Jin-Sheng Wen
In this study, we set out to identify dengue virus serotype 2 (DENV-2)-specific HLA-A*2402-restricted epitopes and determine the characteristics of T cells generated to these epitopes. We screened the full-length amino-acid sequence of DENV-2 to find potential epitopes using the SYFPEITHI algorithm. Twelve putative HLA-A*2402-binding peptides conserved in hundreds of DENV-2 strains were synthesized, and the HLA restriction of peptides was tested in HLA-A*2402 transgenic mice. Nine peptides (NS4b(228-237), NS2a(73-81), E(298-306), M(141-149), NS4a(96-105), NS4b(159-168), NS5(475-484), NS1(162-171), and NS5(611-620)) induced high levels of peptide-specific IFN-γ-secreting cells in HLA-A*2402 transgenic mice...
January 22, 2015: Virus Research
Xuping Xie, Jing Zou, Chunya Puttikhunt, Zhiming Yuan, Pei-Yong Shi
UNLABELLED: Flavivirus nonstructural protein 2A (NS2A) plays important roles in both viral RNA synthesis and virion assembly. The molecular details of how the NS2A protein modulates the two distinct events have not been defined. To address this question, we have performed a systematic mutagenesis of NS2A using dengue virus (DENV) serotype 2 (DENV-2) as a model. We identified two sets of NS2A mutations with distinct defects during a viral infection cycle. One set of NS2A mutations (D125A and G200A) selectively abolished viral RNA synthesis...
January 15, 2015: Journal of Virology
Henrique Nemésio, José Villalaín
The Dengue virus (DENV) NS2A protein, essential for viral replication, is a poorly characterized membrane protein. NS2A displays both protein/protein and membrane/protein interactions, yet neither its functions in the viral cycle nor its active regions are known with certainty. To highlight the different membrane-active regions of NS2A, we characterized the effects of peptides derived from a peptide library encompassing this protein's full length on different membranes by measuring their membrane leakage induction and modulation of lipid phase behavior...
August 28, 2014: Journal of Physical Chemistry. B
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