dengue virus nonstructural-1 protein (NS1) generatesantibodies to common epitopes on human blood clotting,integrin/adhesin proteins and binds to humanendothelial cells: potential implications in haemorrhagic fever pathogenesis

Antibody responses generated by mice to the dengue-2 virus NS1 protein (D-2V NS1) were influenced by MHC class II (I-A) haplotype but each antiserum cross-reacted with human fibrinogen, thrombocytes and endothelial cells. To investigate these findings, a highly avid subclone (MAb 1G5.4-A1-C3) was se...

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Bibliographic Details
Published in:Archives of virology 1997-05, Vol.142 (5), p.897-916
Main Author: Falconar, A. K. I
Format: Article
Language:English
Subjects:
active sites
antibodies
antiserum
Blood
blood coagulation factors
dengue
Dengue fever
Dengue virus
Dengue virus type 2
endothelial cells
epitopes
fibrinogen
haplotypes
hemorrhage
humans
hybridomas
mice
Pathogenesis
Proteins
serotypes
synthetic peptides
viruses
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Summary:Antibody responses generated by mice to the dengue-2 virus NS1 protein (D-2V NS1) were influenced by MHC class II (I-A) haplotype but each antiserum cross-reacted with human fibrinogen, thrombocytes and endothelial cells. To investigate these findings, a highly avid subclone (MAb 1G5.4-A1-C3) was selected from a parent hybridoma that secreted a monoclonal antibody (MAb) specific for the native dimeric form of D-2V NS1. When MAb reactions were compared using a panel of overlapping synthetic peptides covering the entire protein sequence, dimer specificity was found to be a weak reaction with multiple ELK-type motifs present in either the positive (E/D-hydrophobic-K/R) or negative (K/R-hydrophobic-D/E) orientations. MAb 1G5.4-A1-C3 and highly avid anti-NS1 polyclonal antisera reacted with the NS1 proteins of the four dengue virus serotypes, but only weakly reacted with the NS1 proteins of the other flaviviruses. MAb 1G5.4-A1-C3 and several other anti-NS1 MAbs produced haemorrhage in mice, cross-reacted with human fibrinogen, thrombocytes and endothelial cells, with known epitopes or active sites on human clotting factors and integrin/adhesin proteins present on these cells. D-2V NS1 bound to human endothelial cells via a site within its N-terminal region, which led to significantly increased binding of avid anti-NS1 antibodies. These results identified a potential role of both ‘antigenic’ and ‘biochemical’ mimicry in dengue haemorrhagic fever pathogenesis, consistent with clinical data.
ISSN:0304-8608
1432-8798
DOI:10.1007/s007050050127