During the secondary infection, dengue fever progresses to severe dengue haemorrhagic fever dhf and dengue shock syndrome dss 6. Severe dengue most commonly occurs among infants and patients with secondary dengue virus denv infections i. Disease caused by dengue virus is a global health concern with up to 390 million individuals infected annually worldwide. It is a mosquitoborne, single positivestranded rna virus of the family flaviviridae. The three e monomers per icosahedral asymmetric unit do not have.
The main vector of dengue in america is the mosquito aedes aegypti, which is infected by dengue virus denv through receptors of midgut epithelial cells. Each year, an estimated 390 million people are infected. Proteomic identification of dengue virus binding proteins. Transmission dengue virus can be transmitted from the bite of an infected aedes mosquito. Cultured cells infected with these recombinants expressed immunologically reactive flavivirus structural. Differential proteomic analysis of virusenriched fractions. Jan 17, 2020 dengue virus denv is the cause of dengue fever. The envelope protein e of dengue virus binds to receptors present on the host cells through its domain iii that has been primarily recognized to bind cell receptors. Dengue virus denv causes an estimated 390 million infections worldwide annually, with severe forms of disease marked by vascular leakage.
Background dengue fever has rapidly manifested into a serious global health concern. Clinical manifestations of dengue virus infection 8 1. This animation zooms into a 3d model of dengue virus, moving from the viruss outer structures to its inner core. We report the solution structure of the 200residue homodimer of dengue 2 c. Expression of the structural proteins of dengue 2 virus and. All the 95 genomes and 94 proteomes were taken from five groups of viruses, i. Dengue virus denv of flaviviridae family has emerged as the fatal pathogen, which is transmitted in human population by the nimble daybiting of aedes aegypti female mosquito and causes a serious health problem called dengue fever. Dengue virus is a small virus that carries a single strand of rna as its genome. Prevalence of host proteins in the virus, might also suggest howthe virus. Keywords dengue virus denv quantitative proteomics virus host interaction protein expression protein phosphorylation introduction dengue virus denv belongs to the genus flavivirus in the family flaviviridae, which is a large group of singlestranded, positivesense rna viruses.
Hepg2 cells were infected with dengue virus serotype 2 den2 at multiplicity of infection. To increase our understanding of the interaction of dengue virus with the host cell, we analyzed changes in the proteome of human a549 cells in response to. Although vaccines are currently under development, none are available to the general population. Dengue is an arthropod borne virus belongs to family flaviviridae and genus flavivirus. Dengue virus is transmitted between people by female mosquitoes ades aegypti and ades albopidus, which are found throughout the tropical and subtropical regions.
Dengue fever can be caused by any one of four types of dengue virus. Structural proteomics of dengue virus sciencedirect. Structural and dynamic studies of denv and zikv proteases. Some host cellular proteins were as abundant as viral proteins. Structural proteomics of dengue virus, current opinion in. Dengue virus affects hundreds of millions of people each year around the world, causing a tremendous social and economic impact on affected countries. Uversky2,4,5 1 department of electrical and computer engineering, university of alberta, edmonton, alberta, canada. Although extensive studies have been conducted during the past several decades, the molecular mechanisms underlying vascular leakage in dengue shock syndrome dss remain unclear. The most widely cited hypothesis for this occurrence is antibody dependent enhancement ade of. Dengue virus is responsible for 50100 million infections, resulting in nearly 24,000 deaths annually. Specifically, we focus on the structure of the premembrane protein, prm and its role in virus assembly, the first fulllength structure of a multidomain dengue virus replication protein, ns3, and the recently solved structures of ns5 methyltransferase and polymerase domains. Dengue is a mosquitoborne flavivirus found in tropical and subtropical regions of the world, mostly in urban and semiurban settings.
Structure of dengue virus request pdf researchgate. Aug 01, 2008 structural proteomics of dengue virus perera, rushika. Dengue, severity prognosis, proteomics correspondence. Dengue virus differential proteomics abstract the interaction between dengue virus denv and vector mosquitoes are still poorly understood at present. Both types of dengue fever, dengue hemorrhagic fever and dengue shock syndrome, are deadly infections of five different serotypes of this virus denv 15. Solution structure of dengue virus capsid protein reveals. While in mosquito sample 7 p, 200 kda range protein was present in ovary and mosquito also showed presence of dengue virus. In order to identify potential receptors, proteins from mosquito midgut. Proteomic analysis of host responses in hepg2 cells during. Cell reports article a global interactome map of the dengue virus ns1 identi. However, due to the limited understanding of dengue pathogenesis, no satisfactory therapies to treat nor vaccine to. Dengue is among the most important mosquitoborne viral disease in the world. Nevertheless, scientists understanding of dengue virus may be simplistic, as rather than distinct antigenic groups, a continuum appears to exist.
Methods in this study, bioinformatics tools were used to provide a comprehensive sequence and structural analysis of the two most prominent serotypes of dengue rnadependent rna polymerase. Genomics, proteomics and evolution of dengue virus article pdf available in briefings in functional genomics 164 january 2017 with 333 reads how we measure reads. Genomics, proteomics and evolution of dengue virus. Of the viral nonstructural enzymes, the ns5 rnadependent rna polymerase has been established as a promising target due to its lack of an enzymatic counterpart in mammalian cells and.
Five serotypes of the virus have been found, all of which can cause the full spectrum of disease. The first structure of a flavivirus has been determined by using a combination of cryoelectron microscopy and fitting of the known structure of glycoprotein e into the electron density map. Dengue is a mosquitoborne infection caused by four distinct serotypes of dengue virus, each appearing cyclically in the tropics and subtropics along the equator. There are no vaccines or antiviral compounds available to either prevent or treat dengue disease which may be fatal. The seven non structural proteins ns1, ns2a, ns2b, ns3, ns4a, ns4b, ns5 known as.
Proteomics profiling of host cell response via protein. The flavivirus cdna sequences were expressed under the control of the vaccinia 7. However, its pathogenic mechanisms and pathophysiology are still poorly understood. Kummerer, 2 constance delaugerre,3 philippe roingeard,4 pierreolivier vidalain,5 and ali amara1,6. Noncanonical roles of dengue virus nonstructural proteins. This protein is secreted into the blood during dengue infection. Using bioinformatics tools for the discovery of dengue rna. Denv infection can cause mild dengue fever or severe dengue hemorrhagic fever dhfdengue shock syndrome dss. The disease is caused by four serologically and genetically distinct viruses termed dengue virus denv 1, 2, 3 and 4. Author summary dengue virus denv is a major arthropodborne human pathogen, infecting more than 400 million individuals annually worldwide. Both types of dengue fever, dengue hemorrhagic fever and dengue shock syndrome, are deadly infections of five different serotypes of.
Hemorrhage and vascular leakage are two characteristic symptoms of dhfdss. Dengue virus nonstructural protein 1 modulates infectious. Most of these tests use synthetically labeled antibodies to detect dengue ns1 protein. Structural study of mosquito ovarian proteins participating. Specifically, we focus on the structure of the premembrane protein, prm and its role in virus assembly, the first fulllength structure of a multi. Clinical and laboratory diagnosis of dengue virus infection. Dengue virus infection remains a public health problem worldwide.
You can be infected by at least two if not all four types at different times during your lifetime, but only once by the same type. Ns2bns3pro nonstructural protein 2bnonstructural protein 3 has been approved as prime drug target for the drug discovery against dengue. Dengue virus has singlestranded positivesense rna genome of about 11 kbp long, surrounded by a nucleocapsid and covered by a lipid envelope that contains the viral glycoproteins. Structures are currently not available for the proteins denoted in red. The disease is caused by dengue virus denv, which is a member of the flaviviridae family and contains a positive. We thus performed a proteomics study to characterize responses in human endothelial cells ea. Serotypespecific differences in dengue virus nonstructural protein 5 nuclear localization holger hannemann, poyu sung. Amongst the denv proteins, nonstructural protein 1 ns1 is one of the most enigmatic, being required for rna replication, but also secreted from infected cells to. Sep 07, 20 carries a single stranded rna as its genome. Highthroughput quantitative proteomic analysis of dengue.
However, due to the limited understanding of dengue pathogenesis, no satisfactory therapies to treat. Unstructural biology of the dengue virus proteins fanchi meng1, reaid a. In the last 50 years, dengue incidence has increased 30fold, worldwide. This mosquitoborne virus disease is endemic in over 100 countries and will probably continue spreading, given the observed trend in global warming. Ns1 is detectable during the acute phase of dengue virus infections. Dengue virus denv infection is the most common mosquitotransmitted viral infection. As shown in the animation, the outside of the dengue virus is made up of glycoproteins arranged in geometric patterns of two, three, and fivefold symmetry. In this study, 2d dige combined with ms was used to analyze the differential proteomes of aedes albopictus salivary gland, midgut and c636 cells induced by denv2. Serotypespecific differences in dengue virus nonstructural. Nmr and xray structures are shown for c, prm, e, ns3 fulllength and the ns5 methyltransferase and polymerase domains pdb identifiers. Dengue virus denv infection is responsible for the most significant mosquitoborne viral disease in the world today. Structural proteomics of dengue virus structural proteomics of dengue virus perera, rushika. Dengue is the most widespread mosquitoborne viral disease of public health concern. Ns2bns3pro non structural protein 2bnon structural protein 3 has been approved as prime drug target for the drug discovery against dengue.
Specifically, we focus on the structure of the premembrane protein, prm and its role in virus assembly. It is the fastest spreading vectorborne viral disease and is now endemic in over 100 countries, resulting in 40% of the worlds population living in an area at risk for dengue. This can be explained by the plurality of functions exerted by the few proteins coded by viral genomes, with some of these functions shared among members of a same family, but others being unique for each virus species. The world health organization estimates that the yearly number of dengue cases averages 390 million. One of the main impediments to the successful advancement of these vaccines is the lack of welldefined immune correlates of protection. The primary role of capsid is to package the viral genome. Differential proteomic analysis of virusenriched fractions obtained from plasma pools of patients with dengue fever or. Expression of the structural proteins of dengue 2 virus. In this paper, we discuss recent advances in our knowledge of the dengue virus life cycle based on new structural data of the virus and its proteins.
The flaviviridae family comprises a number of human pathogens, which, although sharing structural and functional features, cause diseases with very different outcomes. Sep 16, 2016 all the 95 genomes and 94 proteomes were taken from five groups of viruses, i. Endothelial cells ec are directly responsible for vascular homeostasis and are highly responsive to circulating mediators but are not commonly infected. Denv infection can cause mild dengue fever or severe dengue hemorrhagic fever dhf dengue shock syndrome dss. Each denv has four or more genetic groups or genotypes. Vaccinia virus recombinants were constructed which contained cdna sequences encoding the structural region of dengue 2 virus pr159s1 strain or yellow fever virus 17d strain. Differential proteomics of aedes albopictus salivary gland. Prognostication of disease severity is urgently required to improve patient management. Alterations in actin cytoskeletal assembly and junctional. So far, there is no antiviral drug available against dengue, but a vaccine has been recently marketed. In order to identify potential receptors, proteins from mosquito. Ns1 tests detect the nonstructural protein ns1 of dengue virus. Structural and dynamic studies of denv and zikv proteases and. Structural proteins vanderbilt university medical center.
Antibody recognition of the dengue virus proteome and. Proteomic analysis reveals the enhancement of human serum. A global interactome map of the dengue virus ns1 identifies. Author links open overlay panel rushika perera richard j kuhn. Denv is transmitted to humans by the mosquito vector aedes aegypti and is the most prevalent arbovirus in tropical and subtropical areas. Differential proteomics of aedes albopictus salivary gland, midgut and c636 cell induced by dengue virus infection meichun zhanga,b,c, xiaoying zhenga,b,yuwua,b, ming gana,b,aihea,b, zhuoya lia,b, dongjing zhanga,b, xiansheng wua,b, ximei zhana,b,n a department of parasitology, zhongshan school of medicine, sun yatsen university, guangzhou 510080, peoples republic of china. Dengue virus 1 den1 was first discovered in japan in the 1940s. The other three viruses, den2, den3, and den4, are closely related to den1, but are not recognized as the same virus by. Dengue virus nonstructural protein 1 activates the p38. Dengue virus nonstructural protein 1 activates the p38 mapk. Zikv, like other flaviviridae west nile virus, dengue virus, japanese encephalitis virus and yellow fever virus, is an ar. Agency for science, technology and research, singapore. Flaviviruses are the most medically relevant group of arboviruses causing a wide range of diseases in humans and are associated with high mortality and morbidity, as such posing a major health concern. Denv contains 10 723 nucleotides in a singlestrand positive rna genome, which encodes a large polyprotein precursor of 3391 aminoacid residues.
In some patients, endothelial cell and platelet dysfunction lead to lifethreatening hemorrhagic dengue fever or dengue shock syndrome. Dengue is an important mosquitoborne disease and a global public health problem. The field of bioinformatics has evolved greatly over recent decades, with updated drug design tools now being publically available. Three of these are structural proteins that form the coat of the virus and deliver the rna to target cells, and seven of them are nonstructural proteins that orchestrate the production of new viruses once the virus gets inside the cell. Specifically, we focus on the structure of the premembrane protein, prm and its role in virus assembly, the first.
Vascular leakage is a hallmark of severe dengue infection. Like other flaviviruses, its genome comprises a single strand of positivesense rna encoding 3 structural and 7 nonstructural ns proteins. The virus core, within a lipid bilayer, has a lessordered structure than the external, icosahedral scaffold of 90 glycoprotein e dimers. Out of which 3 are structural proteins and 7 are non structural proteins. Pdf genomics, proteomics and evolution of dengue virus. The capsid c protein of dengue virus is essential for speci.
Nmr and xray structures are shown for c, prm, e, ns3. Dengue virus denv and zika virus zikv belong to flaviviridae family which contains important human pathogens. Chasing intracellular zika virus using proteomics mdpi. Request pdf structural proteomics of dengue virus in this paper, we discuss recent advances in our knowledge of the dengue virus life cycle based on new structural data of the virus and its. The emergence of various viral serotypes has prompted the urgent need for innovative drug design techniques. A risk to anyone traveling to a tropical or subtropical region of the world where dengue virus is found.
Proteomic identification of dengue virus binding proteins in. We performed proteomic analysis to evaluate early host responses as indicated by altered proteins in human target cells during dengue virus infection. One of the host cell proteins pointed to sites in the cell where viruses are assembled. Research article proteomics profiling of host cell response via protein expression and phosphorylation upon dengue virus infection meng miao1 fei yu1,2 danya wang1,2 yongjia tong1,2 liuting yang1,2 jiuyue xu3 yang qiu3 xi zhou1,3 xiaolu zhao1,2 received. Properties and functions of the dengue virus capsid protein. Amongst the denv proteins, non structural protein 1 ns1 is one of the most enigmatic, being required for rna replication, but also secreted from infected cells to. Both types of dengue fever, dengue hemorrhagic fever and dengue shock syndrome, are deadly infections of five different serotypes of this virus.
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