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Antibody responses are generated to immunodominant ELK/KLE-type motifs on the nonstructural-1 glycoprotein during live dengue virus infections in mice and humans: implications for diagnosis, pathogenesis, and vaccine design.
Clin Vaccine Immunol. 2007 May; 14(5):493-504.CV

Abstract

Antibodies generated to the purified dengue type 2 virus (D-2V) nonstructural-1 (NS1) protein in mice and rabbits were compared with those generated to this protein in congeneic (H-2 class II) mouse strains and humans after D-2V infections. Unlike the profiles observed with the rabbits, similar antibody reaction profiles were generated by mice and humans with severe D-2V disease (dengue hemorrhagic fever [DHF]/dengue shock syndrome [DSS]). Many of these epitopes contained the core acidic-hydrophobic-basic (tri-amino-acid; ELK-type) motifs present in the positive or negative orientations. Antibody responses generated to these ELK/KLE-type motifs and the epitope LX1 on this protein were influenced by class II molecules in mice during D-2V infections; but these antibodies cross-reacted with human fibrinogen and platelets, as implicated in DHF/DSS pathogenesis. The core LX1 epitope (113YSWKTWG119), identified by the dengue virus complex-specific monoclonal antibody (MAb) 3D1.4, was prepared so that it contained natural I-Ad-binding and ELK-type motifs. This AFLX1 peptide, which appropriately displayed the ELK-type and LX1 epitopes in solid-phase immunoassays, generated a similar, but lower, immunodominant anti-ELK-motif antibody reaction in I-Ad-positive mice, as generated in mice and humans during D-2V infections. These antibody responses were much stronger in the high-responding mouse strains and each of the DHF/DSS patients tested and may therefore account for the association of DHF/DSS resistance or susceptibility with particular class II molecules and autoantibodies, antibody-stimulating cytokines (e.g., interleukin-6), and complement product C3a being implicated in DHF/DSS pathogenesis. These results are likely to be important for the design of a safe vaccine against this viral disease and showed the AFLX1 peptide and MAb 3D1.4 to be valuable diagnostic reagents.

Authors+Show Affiliations

Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, UK. afalconar@uninorte.edu.co

Pub Type(s)

Clinical Trial
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17329445

Citation

Falconar, Andrew K I.. "Antibody Responses Are Generated to Immunodominant ELK/KLE-type Motifs On the Nonstructural-1 Glycoprotein During Live Dengue Virus Infections in Mice and Humans: Implications for Diagnosis, Pathogenesis, and Vaccine Design." Clinical and Vaccine Immunology : CVI, vol. 14, no. 5, 2007, pp. 493-504.
Falconar AK. Antibody responses are generated to immunodominant ELK/KLE-type motifs on the nonstructural-1 glycoprotein during live dengue virus infections in mice and humans: implications for diagnosis, pathogenesis, and vaccine design. Clin Vaccine Immunol. 2007;14(5):493-504.
Falconar, A. K. (2007). Antibody responses are generated to immunodominant ELK/KLE-type motifs on the nonstructural-1 glycoprotein during live dengue virus infections in mice and humans: implications for diagnosis, pathogenesis, and vaccine design. Clinical and Vaccine Immunology : CVI, 14(5), 493-504.
Falconar AK. Antibody Responses Are Generated to Immunodominant ELK/KLE-type Motifs On the Nonstructural-1 Glycoprotein During Live Dengue Virus Infections in Mice and Humans: Implications for Diagnosis, Pathogenesis, and Vaccine Design. Clin Vaccine Immunol. 2007;14(5):493-504. PubMed PMID: 17329445.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antibody responses are generated to immunodominant ELK/KLE-type motifs on the nonstructural-1 glycoprotein during live dengue virus infections in mice and humans: implications for diagnosis, pathogenesis, and vaccine design. A1 - Falconar,Andrew K I, Y1 - 2007/02/28/ PY - 2007/3/3/pubmed PY - 2007/6/15/medline PY - 2007/3/3/entrez SP - 493 EP - 504 JF - Clinical and vaccine immunology : CVI JO - Clin Vaccine Immunol VL - 14 IS - 5 N2 - Antibodies generated to the purified dengue type 2 virus (D-2V) nonstructural-1 (NS1) protein in mice and rabbits were compared with those generated to this protein in congeneic (H-2 class II) mouse strains and humans after D-2V infections. Unlike the profiles observed with the rabbits, similar antibody reaction profiles were generated by mice and humans with severe D-2V disease (dengue hemorrhagic fever [DHF]/dengue shock syndrome [DSS]). Many of these epitopes contained the core acidic-hydrophobic-basic (tri-amino-acid; ELK-type) motifs present in the positive or negative orientations. Antibody responses generated to these ELK/KLE-type motifs and the epitope LX1 on this protein were influenced by class II molecules in mice during D-2V infections; but these antibodies cross-reacted with human fibrinogen and platelets, as implicated in DHF/DSS pathogenesis. The core LX1 epitope (113YSWKTWG119), identified by the dengue virus complex-specific monoclonal antibody (MAb) 3D1.4, was prepared so that it contained natural I-Ad-binding and ELK-type motifs. This AFLX1 peptide, which appropriately displayed the ELK-type and LX1 epitopes in solid-phase immunoassays, generated a similar, but lower, immunodominant anti-ELK-motif antibody reaction in I-Ad-positive mice, as generated in mice and humans during D-2V infections. These antibody responses were much stronger in the high-responding mouse strains and each of the DHF/DSS patients tested and may therefore account for the association of DHF/DSS resistance or susceptibility with particular class II molecules and autoantibodies, antibody-stimulating cytokines (e.g., interleukin-6), and complement product C3a being implicated in DHF/DSS pathogenesis. These results are likely to be important for the design of a safe vaccine against this viral disease and showed the AFLX1 peptide and MAb 3D1.4 to be valuable diagnostic reagents. SN - 1556-6811 UR - https://www.unboundmedicine.com/medline/citation/17329445/Antibody_responses_are_generated_to_immunodominant_ELK/KLE_type_motifs_on_the_nonstructural_1_glycoprotein_during_live_dengue_virus_infections_in_mice_and_humans:_implications_for_diagnosis_pathogenesis_and_vaccine_design_ L2 - http://cvi.asm.org/cgi/pmidlookup?view=long&pmid=17329445 DB - PRIME DP - Unbound Medicine ER -