Mechanisms of dengue virus neutralization by antibody Public Deposited

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  • March 20, 2019
Creator
  • Wahala, Wahala Mudiyanselage Padmasriri Bandara
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Dengue virus (DENV), the causative agent of dengue, is a group of viruses consisting of four different serotypes designated DENV1-4. Each serotype is further divided into different genotypes. Primary DENV infection induces a life-long type-specific immune response against the homologous DENV serotype. It is widely assumed that all the strains of a DENV serotype are equally neutralized by type-specific antibodies irrespective of the genetic variability within the serotype. Studies with mouse monoclonal antibodies (mAb) have demonstrated that serotype-specific neutralization of DENV is mainly mediated by antibody binding to epitopes on domain III of the viral Envelope protein (EDIII). Although DENV3 has spread worldwide, neutralization mechanisms of DENV3 is poorly studied. Results of my studies with mouse mAbs demonstrate that type-specific neutralization of DENV3 was confined to EDIII lateral ridge as reported for other flaviviruses. I further demonstrated that DENV3 Envelope (E) protein sequences were variable between different genotypes of DENV3. Variable positions were located on or near the known antibody epitopes on E protein, and natural amino acid variations of DENV3 E protein led to complete or partial escape from antibody neutralization. These results suggest that natural intra-serotype variation should be considered when characterizing natural and vaccine induced immunity. The specificity and functionality of the human antibody response to DENV is poorly characterized. It is unknown if humans also develop antibodies to EDIII epitopes recognized by mouse mAbs. Using a panel of sera from people exposed to DENV, I demonstrate that people develop low levels of type-specific EDIII reactive antibodies after primary infection and low levels of serotype cross reactive EDIII antibodies after secondary infection. I further demonstrated that these low levels of EDIII reactive antibodies only make a minor contribution to the total neutralization potency of human immune sera. I conclude that the EDIII epitopes identified using mouse reagents, which have been the focus of much recent work, are not the primary target of human antibodies that neutralize DENV. I believe these results will stimulate investigators to study previously neglected regions of the DENV envelope to identify functionally important epitopes engaged by human antibodies.
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Microbiology and Immunology."
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  • De Silva, Aravinda Manu
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  • Chapel Hill, NC
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  • Open access
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