Dengue virus envelope glycoprotein structure: New insight into its  interactions during viral entry

Rey, F.A.

doi:10.1073/pnas.1332695100

Cited by 89 publications

(51 citation statements)

References 15 publications

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“…Domains I, II, and III (which form the ectodomain) and the C-terminal hydrophobic domain (C-term) of the E protein not only have distinct structural functionalities in the folding and assembly of the protein on the surface of the virion but also elicit substantially different antibody responses in humans (49,50,59). Domain II (EDII) contains the fusion loop responsible for low-pH-mediated fusion with endosomal compartments, while EDIII is a putative receptor-binding domain with an immunoglobulin-like fold, as predicted from E structures in other flaviviruses (8,60,71,78).…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Patterns of Intrahuman Dengue Virus Diversity Reveal Associations with Viral Phylogenetic Clade and Interhost Diversity

Parameswaran

Charlebois

Téllez

et al. 2012

J Virol

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Analogous to observations in RNA viruses such as human immunodeficiency virus, genetic variation associated with intrahost dengue virus (DENV) populations has been postulated to influence viral fitness and disease pathogenesis. Previous attempts to investigate intrahost genetic variation in DENV characterized only a few viral genes or a limited number of full-length genomes. We developed a whole-genome amplification approach coupled with deep sequencing to capture intrahost diversity across the entire coding region of DENV-2. Using this approach, we sequenced DENV-2 genomes from the serum of 22 Nicaraguan individuals with secondary DENV infection and captured ϳ75% of the DENV genome in each sample (range, 40 to 98%). We identified and quantified variants using a highly sensitive and specific method and determined that the extent of diversity was considerably lower than previous estimates. Significant differences in intrahost diversity were detected between genes and also between antigenically distinct domains of the Envelope gene. Interestingly, a strong association was discerned between the extent of intrahost diversity in a few genes and viral clade identity. Additionally, the abundance of viral variants within a host, as well as the impact of viral mutations on amino acid encoding and predicted protein function, determined whether intrahost variants were observed at the interhost level in circulating Nicaraguan DENV-2 populations, strongly suggestive of purifying selection across transmission events. Our data illustrate the value of high-coverage genome-wide analysis of intrahost diversity for high-resolution mapping of the relationship between intrahost diversity and clinical, epidemiological, and virological parameters of viral infection. N early three billion people worldwide are at risk for infection with dengue virus (DENV), a Flavivirus transmitted by the mosquitoes Aedes aegypti and A. albopictus (for reviews, see references 24 and 25). DENV is an RNA virus with a single-stranded, nonsegmented RNA genome ϳ10.7 kb in length, which encodes three structural proteins (capsid [C], premembrane/membrane [prM/M], and envelope ]E]) and seven nonstructural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). There are four closely related serotypes of DENV (DENV-1 to DENV-4) that can cause asymptomatic infections or clinical illnesses ranging from the self-limiting but debilitating dengue fever to the lifethreatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), which are characterized by vascular leakage (76). Even though several factors, such as viral genetics, preexisting heterotypic immunity (i.e., immunity to a different serotype due to a prior infection), the sequence of infection with distinct serotypes, and host genetics appear to influence disease severity (23,35,53,54,58,61,69), the precise causes for progression to severe disease remain unknown.The four DENV serotypes share limited identity, with 25 to 40% variability observed between serotypes at the amino acid level (30, 68)....

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Section: Resultsmentioning

confidence: 99%

Genome-Wide Patterns of Intrahuman Dengue Virus Diversity Reveal Associations with Viral Phylogenetic Clade and Interhost Diversity

Parameswaran

Charlebois

Téllez

et al. 2012

J Virol

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“…Among the many arboviruses, DEN and SINV have been shown to utilize this strategy for viral tropism during vertebrate infection and dissemination (10,60,72). Additionally, there are early indications that N-linked glycosylation patterns on the envelope proteins of both these arboviruses are conserved between early-mosquito-stage virus (i.e., virions taken up in a blood meal from an infected vertebrate host) and virions in the salivary gland (53,77,92). Thus, it is possible that conserved hybrid glycan structures on virus envelope glycoproteins are recognized by C-type lectin-like molecules within the mosquito midgut and other tissues, in a manner similar to the role of DC-SIGN and L-SIGN during viral attachment to vertebrate cells.…”

Section: Bacterial Pathogens the Tick-borne Rickettsial Pathogensmentioning

confidence: 99%

Insight into a Conserved Lifestyle: Protein-Carbohydrate Adhesion Strategies of Vector-Borne Pathogens

Dinglasan

Jacobs-Lorena

2005

Infect Immun

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The incidence of vector-borne diseases such as malaria, dengue, African sleeping sickness, and tick-borne fevers is increasing. Given that current global control efforts have met with limited success, the need to develop novel interventions has become all the more vital. Successful discovery of such interventions is contingent on improving our understanding of how the pathogen interacts with its vertebrate host and also with its invertebrate vector. In this review we examine a premise developed more than 20 years ago (94) that emphasized the role of protein-carbohydrate interactions in microbial pathogenesis, and we present it in the context of vector-pathogen dynamics.Glycans are "essential macromolecules for numerous cellular processes, such as signaling, structural-support, cell-cell interaction, cell-matrix adhesion, growth, protection and trafficking" (94). Their ubiquitous yet tissue-specific occurrence as cell surface glycoconjugates has, over evolutionary time, been exploited by several pathogenic microorganisms as receptors for attachment and invasion (95). While evidence for microbial adherence to mammalian glycolipids and glycoproteins continues to grow (for reviews see references 17, 18, 58, 95, and 115), only recently has evidence for a "protein-carbohydrate recognition strategy" for vector host-pathogen interactions emerged. This review focuses on the most recent advances that describe adherence mechanisms of three different classes of pathogens-bacteria, viruses, and protozoan parasites-to their obligate arthropod vectors. We also discuss how the proteincarbohydrate recognition strategies in both vector and mammalian life stages are apparently conserved and how this conservation could lead to the development of novel strategies for intervention.

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“…The immature virion, which lacks cleavage of the prM protein, has a rough surface with 60 spikes (79), whereas the mature virion has a smooth surface. X-ray crystallographic analyses of the soluble ectodomains of the E proteins from tick-borne encephalitis virus and DENV demonstrated a dimeric assembly, with each subunit containing three domains (46,59,60). Domain III (DIII), which adopts an immunoglobulin-like fold, is believed by some to contain a cell surface receptor recognition site (3,60,74,77).…”

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confidence: 99%

Type- and Subcomplex-Specific Neutralizing Antibodies against Domain III of Dengue Virus Type 2 Envelope Protein Recognize Adjacent Epitopes

Sukupolvi-Petty

Austin

Purtha

et al. 2007

J Virol

237

331

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Neutralization of flaviviruses in vivo correlates with the development of an antibody response against the viral envelope (E) protein. Previous studies demonstrated that monoclonal antibodies (MAbs) against an epitope on the lateral ridge of domain III (DIII) of the West Nile virus (WNV) E protein strongly protect against infection in animals.Based on X-ray crystallography and sequence analysis, an analogous type-specific neutralizing epitope for individual serotypes of the related flavivirus dengue virus (DENV) was hypothesized. Using yeast surface display of DIII variants, we defined contact residues of a panel of type-specific, subcomplex-specific, and cross-reactive MAbs that recognize DIII of DENV type 2 (DENV-2) and have different neutralizing potentials. Type-specific MAbs with neutralizing activity against DENV-2 localized to a sequence-unique epitope on the lateral ridge of DIII, centered at the FG loop near residues E383 and P384, analogous in position to that observed with WNV-specific strongly neutralizing MAbs. Subcomplex-specific MAbs that bound some but not all DENV serotypes and neutralized DENV-2 infection recognized an adjacent epitope centered on the connecting A strand of DIII at residues K305, K307, and K310. In contrast, several MAbs that had poor neutralizing activity against DENV-2 and cross-reacted with all DENV serotypes and other flaviviruses recognized an epitope with residues in the AB loop of DIII, a conserved region that is predicted to have limited accessibility on the mature virion. Overall, our experiments define adjacent and structurally distinct epitopes on DIII of DENV-2 which elicit type-specific, subcomplex-specific, and cross-reactive antibodies with different neutralizing potentials.Dengue fever (DF), the most prevalent arthropod-borne viral illness in humans, is caused by dengue virus (DENV). The four serotypes of DENV are transmitted to humans primarily by the mosquitoes Aedes aegypti and Aedes albopictus. DENV is a member of the Flaviviridae family and is related to the viruses that cause yellow fever and the Japanese, St. Louis, and West Nile encephalitides (8). Infection by DENV causes a spectrum of clinical disease, ranging from an acute, debilitating, selflimited febrile illness (DF) to a life-threatening hemorrhagic and capillary leak syndrome (dengue hemorrhagic fever/dengue shock syndrome). At present, no approved antiviral treatment or vaccine is available, and therapy is supportive in nature. DENV causes an estimated 25 to 100 million cases of DF and 250,000 cases of dengue hemorrhagic fever per year worldwide, with 2.5 billion people at risk for infection (27,48).DENV is an enveloped virus with a single-stranded, positivesense RNA genome (11). The 10.7-kilobase genome is translated as a single polyprotein, which is then cleaved into three structural proteins (C, prM/M, and E) and seven nonstructural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) by virus-and host-encoded proteases. The 500-Å DENV mature virion has a well-organized outer protein she...

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Dengue virus envelope glycoprotein structure: New insight into its interactions during viral entry

Cited by 89 publications

References 15 publications

Genome-Wide Patterns of Intrahuman Dengue Virus Diversity Reveal Associations with Viral Phylogenetic Clade and Interhost Diversity

Genome-Wide Patterns of Intrahuman Dengue Virus Diversity Reveal Associations with Viral Phylogenetic Clade and Interhost Diversity

Insight into a Conserved Lifestyle: Protein-Carbohydrate Adhesion Strategies of Vector-Borne Pathogens

Type- and Subcomplex-Specific Neutralizing Antibodies against Domain III of Dengue Virus Type 2 Envelope Protein Recognize Adjacent Epitopes

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