A Highly Conserved Region Between Amino Acids 221 and 266 of Dengue Virus Non-Structural Protein 1 is a Major Epitope Region in Infected Patients

Omokoko, Magot Diata; Pambudi, Sabar; Phanthanawiboon, Supranee; Masrinoul, Promsin; Setthapramote, Chayanee; Sasaki, Tadahiro; Kuhara, Motoki; Ramasoota, Pongrama; Yamashita, Akifumi; Hirai, Itaru; Ikuta, Kazuyoshi; Kurosu, Takeshi

doi:10.4269/ajtmh.13-0624

Cited by 15 publications

(11 citation statements)

References 48 publications

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“…However, a recent report showed that NS1-immune polyclonal mouse serum or monoclonal antibodies to NS1, and immunization with NS1 protected mice against DENV-2 in a lethal challenge model [ 23 ], suggesting a role for anti-NS1 antibodies in protection from disease. One of our NS1 epitopes ( Fig 5D–5F , Peak D) was recently identified as a target of human anti-NS1 monoclonal antibodies [ 24 ]. In that report, nine human monoclonal antibodies to NS1 from patients secondarily infected with DENV-2 bound to a common epitope located between amino acids 221–266.…”

Section: Discussionmentioning

confidence: 99%

Pathogen-specific deep sequence-coupled biopanning: A method for surveying human antibody responses

et al. 2017

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Identifying the targets of antibody responses during infection is important for designing vaccines, developing diagnostic and prognostic tools, and understanding pathogenesis. We developed a novel deep sequence-coupled biopanning approach capable of identifying the protein epitopes of antibodies present in human polyclonal serum. Here, we report the adaptation of this approach for the identification of pathogen-specific epitopes recognized by antibodies elicited during acute infection. As a proof-of-principle, we applied this approach to assessing antibodies to Dengue virus (DENV). Using a panel of sera from patients with acute secondary DENV infection, we panned a DENV antigen fragment library displayed on the surface of bacteriophage MS2 virus-like particles and characterized the population of affinity-selected peptide epitopes by deep sequence analysis. Although there was considerable variation in the responses of individuals, we found several epitopes within the Envelope glycoprotein and Non-Structural Protein 1 that were commonly enriched. This report establishes a novel approach for characterizing pathogen-specific antibody responses in human sera, and has future utility in identifying novel diagnostic and vaccine targets.

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Section: Discussionmentioning

confidence: 99%

Pathogen-specific deep sequence-coupled biopanning: A method for surveying human antibody responses

et al. 2017

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“…Additionally, the structure of the DENV2 β‐ladder in complex with the Fab of a neutralizing antibody (22NS1) is consistent with this hexamer arrangement (Figure C), as the 22NS1 epitope is on the hexamer exterior. The 22NS1 epitope overlaps with epitopes mapped for human patient antibodies showing that the hexamer exterior is recognized by secondarily infected dengue patients . Additionally, regions of NS1, which are most varied among the four major dengue serotypes, map almost exclusively to the outer face (Figure ).…”

Section: The Ns1 Hexamer Exposes An Outer Variable Facementioning

confidence: 97%

Structure‐guided insights on the role of NS1 in flavivirus infection

et al. 2015

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We highlight the various domains of the flavivirus virulence factor NS1 and speculate on potential implications of the NS1 3D structure in understanding its role in flavivirus pathogenesis. Flavivirus non-structural protein 1 (NS1) is a virulence factor with dual functions in genome replication and immune evasion. Crystal structures of NS1, combined with reconstructions from electron microscopy (EM), provide insight into the architecture of dimeric NS1 on cell membranes and the assembly of a secreted hexameric NS1-lipid complex found in patient sera. Three structural domains of NS1 likely have distinct roles in membrane association, replication complex assembly, and immune system avoidance. A conserved hydrophobic inner face is sequestered either on the membrane or in the interior of the secreted hexamer and contains regions implicated in viral replication. The exposed variable outer face is presented to cellular and secreted components of the immune system in infected patients and contains candidate regions for immune system modulation. We anticipate that knowledge of the distinct NS1 domains and assembly will lead to advances in elucidating virus-host interactions mediated through NS1 and in dissecting the role of NS1 in viral genome replication.

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“… ( a ) Schematic representation of DENV2 ΔNS1. DENV2 ΔNS1 lacks the following antigenic regions from full-length DENV2 NS1 that potentially elicit the production of cross-reactive antibodies: amino acids 116–119 14 , 221–266 15 and 311–330 16 . …”

Section: Figurementioning

confidence: 99%

Flavivirus NS1 protein in infected host sera enhances viral acquisition by mosquitoes

et al. 2016

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SummaryThe arbovirus life cycle involves viral transfer between a vertebrate host and an arthropod vector, and acquisition of virus from an infected mammalian host by a vector is an essential step in this process. Here, we report that flavivirus nonstructural protein-1 (NS1), which is abundantly secreted into the serum of an infected host, plays a critical role in flavivirus acquisition by mosquitoes. The presence of dengue virus (DENV) and Japanese encephalitis virus (JEV) NS1s in the blood of infected interferon alpha and gamma receptor-deficient mice (AG6) facilitated virus acquisition by their native mosquito vectors because the protein enabled the virus to overcome the immune barrier of the mosquito midgut. Active immunization of AG6 mice with a modified DENV NS1 reduced DENV acquisition by mosquitoes and protected mice against a lethal DENV challenge, suggesting that immunization with NS1 could reduce the number of virus-carrying mosquitoes as well as the incidence of flaviviral diseases. Our study demonstrates that flaviviruses utilize NS1 proteins produced during their vertebrate phases to enhance their acquisition by vectors, which might be a result of flavivirus evolution to adapt to multiple host environments.

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A Highly Conserved Region Between Amino Acids 221 and 266 of Dengue Virus Non-Structural Protein 1 is a Major Epitope Region in Infected Patients

Cited by 15 publications

References 48 publications

Pathogen-specific deep sequence-coupled biopanning: A method for surveying human antibody responses

Pathogen-specific deep sequence-coupled biopanning: A method for surveying human antibody responses

Structure‐guided insights on the role of NS1 in flavivirus infection

Flavivirus NS1 protein in infected host sera enhances viral acquisition by mosquitoes

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