Dengue is an emerging mosquito-borne viral infection of humans. Infected people develop potent and long lasting antibodies (Abs) that neutralize the homologous dengue virus (DENV) serotype. Paradoxically, Abs have also been implicated in enhanced viral replication and more severe disease. Despite the evidence that Abs are important in dengue pathogenesis, we are just beginning to learn about the binding and functional properties of the human Ab response to DENV. The humoral immune response to a pathogen is derived from long-lived plasma cells (LLPCs) that contribute to circulating Abs and a memory B cell (MBC) pool that is activated upon re-exposure to the pathogen. While it is known that DENV infection stimulates robust LLPC and MBC responses, specific properties of Abs derived from these two compartments have not been characterized in detail. Based on recent findings from our group and others, we propose to test the hypothesis that new epitopes created by close packing of envelope (E) protein molecules on the viral surface are the main target of the human DENV serotype-specific neutralizing Ab response. People exposed to primary DENV infections develop long-term serotype specific neutralizing Ab responses whereas secondary infections result in serotype cross neutralizing responses. We propose that second infections preferentially activate somatically mutated MBCs expressing Abs that bind with high affinity to 2 or more serotypes and are capable of cross neutralizing serotypes. We propose three specific aims to characterize neutralizing antibodies derived from MBC and LLPCs after primary infections (Aims 1 and 2) and secondary infections (Aim 3). The impact of this work will be far ranging as it will redirect a field that has mainly focused on B cell epitope on subunits of E protein to consider new structural features and epitopes created following viral assembly. These studies proposed here are directly relevant to developing simple assays to predict the performance of the leading dengue vaccine candidates and also for developing the next generation of safe and effective dengue vaccines. .
Dengue is the most significant mosquito transmitted viral infection of humans. Vaccination is a feasible solution to prevent and control dengue. However, dengue vaccines need to be developed with caution because of evidence that antibodies against dengue virus can prevent or enhance disease. We propose to study the human antibody response to dengue virus and describe the specific mechanisms by which human antibodies neutralize the virus. Our results will help to evaluate vaccine currently under development and to develop the next generation vaccines.
|Zhang, Shuijun; Kostyuchenko, Victor A; Ng, Thiam-Seng et al. (2016) Neutralization mechanism of a highly potent antibody against Zika virus. Nat Commun 7:13679|
|Swanstrom, J A; Plante, J A; Plante, K S et al. (2016) Dengue Virus Envelope Dimer Epitope Monoclonal Antibodies Isolated from Dengue Patients Are Protective against Zika Virus. MBio 7:|
|Messer, William B; Yount, Boyd L; Royal, Scott R et al. (2016) Functional Transplant of a Dengue Virus Serotype 3 (DENV3)-Specific Human Monoclonal Antibody Epitope into DENV1. J Virol 90:5090-7|
|Fibriansah, Guntur; Ibarra, Kristie D; Ng, Thiam-Seng et al. (2015) DENGUE VIRUS. Cryo-EM structure of an antibody that neutralizes dengue virus type 2 by locking E protein dimers. Science 349:88-91|
|Smith, Scott A; Nivarthi, Usha K; de Alwis, Ruklanthi et al. (2015) Dengue Virus prM-Specific Human Monoclonal Antibodies with Virus Replication-Enhancing Properties Recognize a Single Immunodominant Antigenic Site. J Virol 90:780-9|
|Gallichotte, E N; Widman, D G; Yount, B L et al. (2015) A new quaternary structure epitope on dengue virus serotype 2 is the target of durable type-specific neutralizing antibodies. MBio 6:e01461-15|
|Fibriansah, Guntur; Tan, Joanne L; Smith, Scott A et al. (2015) A highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins. Nat Commun 6:6341|
|Messer, William B; de Alwis, Ruklanthi; Yount, Boyd L et al. (2014) Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity. Proc Natl Acad Sci U S A 111:1939-44|
|Fibriansah, Guntur; Tan, Joanne L; Smith, Scott A et al. (2014) A potent anti-dengue human antibody preferentially recognizes the conformation of E protein monomers assembled on the virus surface. EMBO Mol Med 6:358-71|
|de Alwis, Ruklanthi; Williams, Katherine L; Schmid, Michael A et al. (2014) Dengue viruses are enhanced by distinct populations of serotype cross-reactive antibodies in human immune sera. PLoS Pathog 10:e1004386|
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