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.
|Metz, Stefan W; Thomas, Ashlie; Brackbill, Alex et al. (2018) Nanoparticle delivery of a tetravalent E protein subunit vaccine induces balanced, type-specific neutralizing antibodies to each dengue virus serotype. PLoS Negl Trop Dis 12:e0006793|
|Adams Waldorf, Kristina M; Nelson, Branden R; Stencel-Baerenwald, Jennifer E et al. (2018) Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain. Nat Med 24:368-374|
|Gallichotte, Emily N; Baric, Thomas J; Yount Jr, Boyd L et al. (2018) Human dengue virus serotype 2 neutralizing antibodies target two distinct quaternary epitopes. PLoS Pathog 14:e1006934|
|de Silva, Aravinda M; Harris, Eva (2018) Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination? The Path to a Dengue Vaccine: Learning from Human Natural Dengue Infection Studies and Vaccine Trials. Cold Spring Harb Perspect Biol 10:|
|Premkumar, Lakshmanane; Collins, Matthew; Graham, Stephen et al. (2018) Development of Envelope Protein Antigens To Serologically Differentiate Zika Virus Infection from Dengue Virus Infection. J Clin Microbiol 56:|
|Pantoja, Petraleigh; Pérez-Guzmán, Erick X; Rodríguez, Idia V et al. (2017) Zika virus pathogenesis in rhesus macaques is unaffected by pre-existing immunity to dengue virus. Nat Commun 8:15674|
|Liu, Ping; Ridilla, Marc; Patel, Pratik et al. (2017) Beyond attachment: Roles of DC-SIGN in dengue virus infection. Traffic 18:218-231|
|Collins, Matthew H; McGowan, Eileen; Jadi, Ramesh et al. (2017) Lack of Durable Cross-Neutralizing Antibodies Against Zika Virus from Dengue Virus Infection. Emerg Infect Dis 23:773-781|
|Liu, Ping; Weinreb, Violetta; Ridilla, Marc et al. (2017) Rapid, directed transport of DC-SIGN clusters in the plasma membrane. Sci Adv 3:eaao1616|
|Gallichotte, Emily N; Menachery, Vineet D; Yount Jr, Boyd L et al. (2017) Epitope Addition and Ablation via Manipulation of a Dengue Virus Serotype 1 Infectious Clone. mSphere 2:|
Showing the most recent 10 out of 28 publications