Fusion Loop Peptide of the West Nile Virus Envelope Protein Is Essential for Pathogenesis and Is Recognized by a Therapeutic Cross-Reactive Human Monoclonal Antibody
| Autor: | Theodore Oliphant, Hameeda Sultana, Michael Engle, Harald G. Foellmer, Nathalie Bonafé, Wayne A. Marasco, Paul Kaplan, Michel Ledizet, Raymond A. Koski, Manoj N. Krishnan, Michael S. Diamond, Erol Fikrig, Girish Neelakanta, Karen Anthony, Ruth R. Montgomery |
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| Rok vydání: | 2009 |
| Předmět: |
medicine.drug_class
Recombinant Fusion Proteins viruses Viral pathogenesis Immunology Virulence Cross Reactions Dengue virus Biology medicine.disease_cause Monoclonal antibody Article Neutralization Epitope Cell Line Dengue fever Mice Viral Envelope Proteins medicine Animals Humans Immunology and Allergy Mice Inbred BALB C Antibodies Monoclonal Dengue Virus medicine.disease Virology Protein Structure Tertiary Mice Inbred C57BL Epitope mapping Female Binding Sites Antibody Peptides Viral Fusion Proteins West Nile virus West Nile Fever |
| Zdroj: | The Journal of Immunology. 183:650-660 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | West Nile virus is an emerging pathogen that can cause fatal neurological disease. A recombinant human mAb, mAb11, has been described as a candidate for the prevention and treatment of West Nile disease. Using a yeast surface display epitope mapping assay and neutralization escape mutant, we show that mAb11 recognizes the fusion loop, at the distal end of domain II of the West Nile virus envelope protein. Ab mAb11 cross-reacts with all four dengue viruses and provides protection against dengue (serotypes 2 and 4) viruses. In contrast to the parental West Nile virus, a neutralization escape variant failed to cause lethal encephalitis (at higher infectious doses) or induce the inflammatory responses associated with blood-brain barrier permeability in mice, suggesting an important role for the fusion loop in viral pathogenesis. Our data demonstrate that an intact West Nile virus fusion loop is critical for virulence, and that human mAb11 targeting this region is efficacious against West Nile virus infection. These experiments define the molecular determinant on the envelope protein recognized by mAb11 and demonstrate the importance of this region in causing West Nile encephalitis. |
| Databáze: | OpenAIRE |
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