The dengue virus nonstructural-1 protein (NS1) generates antibodies to common epitopes on human blood clotting, integrin/adhesin proteins and binds to human endothelial 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 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.
Falconar
A K
AK
Department of Medical Parasitology, London School of Hygiene and Tropical Medicine, U.K.
D000818:Animals; D000911:Antibodies, Monoclonal; D000917:Antibody Formation; D000956:Antigens, Viral / Q000276:immunology*; D001792:Blood Platelets / Q000276:immunology; D003429:Cross Reactions; D003715:Dengue / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology*; D004730:Endothelium, Vascular / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005340:Fibrinogen / Q000276:immunology*; D006801:Humans; D016023:Integrins / Q000276:immunology*; D051379:Mice; D017361:Viral Nonstructural Proteins / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000956:Antigens, Viral; D000939:Epitopes; D016023:Integrins; C079340:NS1 protein, Dengue virus type 2; D017361:Viral Nonstructural Proteins; D005340:Fibrinogen