Dengue viruses (DENV) are emerging, mosquito-borne Flaviviruses and the agents of dengue fever (DF) and dengue hemorrhagic fever (DHF). The NIAID has listed dengue (DEN) as a category A priority agent with respect to Biodefense and Emerging Infections research. A large body of work has demonstrated that people infected with DENV develop long-term protective immunity to the infecting serotype but not to other serotypes. During a second infection with a different serotype, the risk of severe disease is greater because cross-reactive immunity can exacerbate the disease. Efforts to develop DEN vaccines have been hampered by the dual role of immunity in protection and pathogenesis. We know very little about the antibody repertoire in people who have been infected with dengue. The main goal of this project is to use DENV3 as a model for defining the viral epitopes engaged by human antibody and to determine the functional outcome of these interactions. Our overall hypothesis is that a neutralizing antibody response is directed towards type-specific epitopes on domain III of E protein, whereas a non-neutralizing and potentially pathogenic antibody response is directed towards cross-reactive epitopes on domains I and II of E protein.
In aim 1 tudies will be done to produce human monoclonal antibodies from people who have recovered from DENV nfections.
In aim 2 a selected subset of human MAbs will be mapped to specific epitopes and functionally characterized for neutralizing or enhancing activity using cell culture and an animal model. The current dogma is that the main type-specific neutralization epitopes are conserved within each serotype. Our preliminary studies indicate that surface exposed regions on E protein of DENV3 are highly variable between trains.
In aim 3 we will determine if the main antibody epitopes are conserved among DENV3 strains. This project takes advantage of a panel of reagents including well characterized virus strains, human samples and a DENV3 infectious clone available at UNC. The project also utilizes antibody and protein cores available within SERCEB as well as a new rodent model of DENV developed by a SERCEB investigator. The study is expected to reveal mechanisms of antibody mediated neutralization or enhancement of DENV3. This information is directly applicable to the evaluation of the safety and efficacy of candidate dengue vaccines.

Public Health Relevance

Dengue is an emerging virus responsible for severe disease in tropical countries. The most practical solution to dengue is to develop a safe and effective vaccine. We propose to study how human antibodies neutralize dengue virus. The studies are directly relevant to developing and evaluating vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057157-10
Application #
8375878
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
2012-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
10
Fiscal Year
2012
Total Cost
$262,436
Indirect Cost
$54,684
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Smartt, Chelsea T; Shin, Dongyoung; Alto, Barry W (2017) Dengue serotype-specific immune response in Aedes aegypti and Aedes albopictus. Mem Inst Oswaldo Cruz 112:829-837
Purcell, Erin B; McKee, Robert W; Courson, David S et al. (2017) A Nutrient-Regulated Cyclic Diguanylate Phosphodiesterase Controls Clostridium difficile Biofilm and Toxin Production during Stationary Phase. Infect Immun 85:
Ponnuswamy, Padmapriya; Joffre, Jeremie; Herbin, Olivier et al. (2017) Angiotensin II synergizes with BAFF to promote atheroprotective regulatory B cells. Sci Rep 7:4111
Silva, Laurie A; Dermody, Terence S (2017) Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies. J Clin Invest 127:737-749
Elong Ngono, Annie; Chen, Hui-Wen; Tang, William W et al. (2016) Protective Role of Cross-Reactive CD8 T Cells Against Dengue Virus Infection. EBioMedicine 13:284-293
Bowles, R D; Karikari, I O; VanDerwerken, D N et al. (2016) In vivo luminescent imaging of NF-?B activity and NF-?B-related serum cytokine levels predict pain sensitivities in a rodent model of peripheral neuropathy. Eur J Pain 20:365-76
Rowse, Michael; Qiu, Shihong; Tsao, Jun et al. (2016) Reduction of Influenza Virus Envelope's Fusogenicity by Viral Fusion Inhibitors. ACS Infect Dis 2:47-53
Ashbrook, Alison W; Lentscher, Anthony J; Zamora, Paula F et al. (2016) Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection. MBio 7:
Bates, John T; Pickens, Jennifer A; Schuster, Jennifer E et al. (2016) Immunogenicity and efficacy of alphavirus-derived replicon vaccines for respiratory syncytial virus and human metapneumovirus in nonhuman primates. Vaccine 34:950-6
Alayli, Farah; Scholle, Frank (2016) Dengue virus NS1 enhances viral replication and pro-inflammatory cytokine production in human dendritic cells. Virology 496:227-236

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