Identification of an epitope on the dengue virus membrane (M) protein defined by cross-protective monoclonal antibodies: design of an improved epitope sequence based on common determinants present in both envelope (E and M) proteins

Falconar, Andrew K.

doi:10.1007/s007050050646

Cited by 103 publications

(133 citation statements)

References 26 publications

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“…In clinical, antibodies against prM protein could be used as a diagnostic marker to distinguish previous infection of dengue virus from Japanese encephalitis virus [27] . The M3 epitope which is conserved among all four dengue virus serotypes but not other flavivirus, such as Japanese encephalitis virus, recognized by our own anti-prM antibody was located at the a.a.53-67of the prM protein nearby the prM/M cleavage junction and was different from the published sequence recognized by other anti-prM monoclonal antibody (2H2), 40-PGFTVMAAIL-49 (M40-49) from the first membrane-spanning domain of the M protein [14] . Although our own anti-prM antibody may recognize all four dengue serotypes, this binding was insufficient to inhibit virus infection.…”

Section: Discussioncontrasting

confidence: 78%

“…Antibodies against dengue E proteins were studied extensively, but little is known about anti-prM antibody. Monoclonal anti-prM antibodies have been reported to mediate ADE infection and provide cross-protection against four dengue virus serotypes in vivo [14] . As there are huge amounts of auto-reactive antibodies during dengue virus infection, we extend our previous finding that in addition to mediate ADE infection anti-prM antibody may bind to BHK and A549 cells [15] .…”

Section: Introductionmentioning

confidence: 99%

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Anti-prM Antibody as an Autoantibody in Dengue Virus Infection

Huang¹,

Cheng²,

Lin³

et al. 2008

American J. of Infectious Diseases

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Abstract:We have reported that anti-prM antibody is an enhancing antibody that enhances DV infection of non-Fc receptor bearing cells by dual specificity. We identified the epitope recognized by this anti-prM antibody, M3, which is located at the a.a.53-67of the prM protein nearby the prM/M cleavage junction and these anti-M3 antibodies could be detected in dengue patients sera. Surprisingly, this anti-prM antibody not only recognizes the prM protein of dengue virions, but also cross-reacts with epithelial cells, endothelial cells as well as T cells. The binding of anti-prM antibody to endothelial cells was dose-dependent and could be blocked by M3 peptides. Human M3-specific antibodies from dengue patient sera were demonstrated to be able to bind to endothelial cells and mediate ADE infection on K562 cells. Furthermore, the anti-prM antibody will mediate the antibodydependent cell phagocytosis, leading to the similar severe form of DHF/DSS. In conclusion, anti-prM antibody plays two roles in the pathogenesis of dengue virus infection: to be an enhancing antibody and an autoantibody as well.

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Section: Discussioncontrasting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Anti-prM Antibody as an Autoantibody in Dengue Virus Infection

Huang¹,

Cheng²,

Lin³

et al. 2008

American J. of Infectious Diseases

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“…This incomplete cleavage of prM has also been described previously for other flaviviruses, including DENV (47,52,54,71), WNV (19), Kunjin virus (31), and Langat virus (17,28). The DENV prM/M protein has been shown previously to actively induce protective immunity; the passive administration of anti-prM antibodies protects mice against a lethal challenge (3,14,29,67). Some evidence has suggested that monoclonal antibodies directed against prM provide protective immunity, perhaps because of their cross-reactivity with the E protein (14, 29) or because they are able to neutralize uncleaved prM protein present on the surfaces of the extracellular virions (29).…”

Section: Discussionsupporting

confidence: 66%

A Single N-Linked Glycosylation Site in the Japanese Encephalitis Virus prM Protein Is Critical for Cell Type-Specific prM Protein Biogenesis, Virus Particle Release, and Pathogenicity in Mice

Kim

Yun

Song

et al. 2008

J Virol

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The prM protein of Japanese encephalitis virus (JEV) contains a single potential N-linked glycosylation site, N 15 -X 16 -T 17 , which is highly conserved among JEV strains and closely related flaviviruses. To investigate the role of this site in JEV replication and pathogenesis, we manipulated the RNA genome by using infectious JEV cDNA to generate three prM mutants (N15A, T17A, and N15A/T17A) with alanine substiting for N 15 and/or T 17 and one mutant with silent point mutations introduced into the nucleotide sequences corresponding to all three residues in the glycosylation site. An analysis of these mutants in the presence or absence of endoglycosidases confirmed the addition of oligosaccharides to this potential glycosylation site. The loss of prM N glycosylation, without significantly altering the intracellular levels of viral RNA and proteins, led to an Ϸ20-fold reduction in the production of extracellular virions, which had protein compositions and infectivities nearly identical to those of wild-type virions; this reduction occurred at the stage of virus release, rather than assembly. This release defect was correlated with small-plaque morphology and an N-glycosylation-dependent delay in viral growth. A more conservative mutation, N15Q, had the same effect as N15A. One of the four prM mutants, N15A/T17A, showed an additional defect in virus growth in mosquito C6/36 cells but not human neuroblastoma SH-SY5Y or hamster BHK-21 cells. This cell type dependence was attributed to abnormal N-glycosylationindependent biogenesis of prM. In mice, the elimination of prM N glycosylation resulted in a drastic decrease in virulence after peripheral inoculation. Overall, our findings indicate that this highly conserved N-glycosylation motif in prM is crucial for multiple stages of JEV biology: prM biogenesis, virus release, and pathogenesis.Japanese encephalitis virus (JEV) is a member of the genus Flavivirus, which consists of Ϸ80 enveloped RNA viruses in the family Flaviviridae (5,22,36). The flaviviruses include many other clinically important human pathogens, such as dengue virus (DENV), yellow fever virus, West Nile virus (WNV), St. Louis encephalitis virus, Murray Valley encephalitis virus, and tick-borne encephalitis virus (TBEV). JEV is transmitted in an enzoonotic cycle between mosquito vectors and vertebrate hosts, with pigs and ardeid birds as the primary viremia-amplifying hosts and reservoirs, respectively, and with humans as incidental hosts (4). JEV is the most important cause of epidemic encephalitis in many Asian countries, leading to permanent neuropsychiatric sequelae and even death in children and young adults (13,60,64,66). Over the past two decades, JEV has spread throughout the Indonesian archipelago (9, 75) to the Australian territories (41,42,65), attracting increasing attention in the arena of international public health.JEV contains a single-stranded, positive-sense RNA genome of Ϸ11,000 nucleotides. The RNA genome has a cap structure at the 5Ј end and lacks a poly(A) tail at the 3Ј end (37)...

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“…The majority of flavivirus-neutralizing antibodies recognize the structural E protein, although some also bind to the prM/M pro-tein (16,21,58,73). Serotype-specific epitopes elicit antibodies with the strongest neutralizing activities (62,63), and protection in animals by antibodies correlates with neutralizing activity in vitro (6,20,25,43,53,63).…”

mentioning

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

231

329

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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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Identification of an epitope on the dengue virus membrane (M) protein defined by cross-protective monoclonal antibodies: design of an improved epitope sequence based on common determinants present in both envelope (E and M) proteins

Cited by 103 publications

References 26 publications

Anti-prM Antibody as an Autoantibody in Dengue Virus Infection

Anti-prM Antibody as an Autoantibody in Dengue Virus Infection

A Single N-Linked Glycosylation Site in the Japanese Encephalitis Virus prM Protein Is Critical for Cell Type-Specific prM Protein Biogenesis, Virus Particle Release, and Pathogenicity in Mice

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

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