This project will investigate the role of human antibodies in protection against or enhancement of infection caused by serotype 3 dengue viruses. Pre-existing heterotypic dengue antibody is a risk factor for lifethreatening severe illness, designated dengue hemorrhagic fever (DHF). Although it is well established that the induction of heterotypic dengue antibodies can predispose subjects to DHF, the molecular basis for this problem is not well understood. This issue is a major obstacle to effective development of dengue vaccines as it is not clear that tetravalent vaccine formulations can be established that always retain the immunogenicity of all four serotypes. Better knowledge of the molecular basis of antibody-mediated neutralization of infection is needed. In the work proposed in this application, we will derive large panels of human monoclonal antibodies directed to dengue virus serotype 3 from the B cells of subjects previously infected with that virus. In previous work funded by the RCE, we have developed a very reliable and robust method for generating human monoclonal antibody secretign hybridoma lines from immune donors. We will determine the genetic and structural basis for effective neutralization of dengue viruses by sequence analysis of antibodies, generation of recombinant antibodies for study of naturally occurring somatic mutations, generation of escape mutant viruses, definition of determinants of components of affinity (on and off rates), and determination of structures of immunodominant antibodies bound to viral antigens.
This project is highly relevant to the goals of the SERCEB RCE, specifically defining important mechanisms of immunity to a virus that is a major cause of human illness (approximately 100 million febrile illnesses a year worldwide).
|Ashbrook, Alison W; Lentscher, Anthony J; Zamora, Paula F et al. (2016) Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection. MBio 7:|
|Bowles, R D; Karikari, I O; VanDerwerken, D N et al. (2016) In vivo luminescent imaging of NF-ÎºB activity and NF-ÎºB-related serum cytokine levels predict pain sensitivities in a rodent model of peripheral neuropathy. Eur J Pain 20:365-76|
|Alayli, Farah; Scholle, Frank (2016) Dengue virus NS1 enhances viral replication and pro-inflammatory cytokine production in human dendritic cells. Virology 496:227-36|
|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|
|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|
|de St Maurice, Annabelle; Grijalva, Carlos G; Fonnesbeck, Christopher et al. (2015) Racial and Regional Differences in Rates of Invasive Pneumococcal Disease. Pediatrics 136:e1186-94|
|Roberts, Lydia M; Ledvina, Hannah E; Tuladhar, Shraddha et al. (2015) Depletion of alveolar macrophages in CD11c diphtheria toxin receptor mice produces an inflammatory response. Immun Inflamm Dis 3:71-81|
|Smith, Scott A; Silva, Laurie A; Fox, Julie M et al. (2015) Isolation and Characterization of Broad and Ultrapotent Human Monoclonal Antibodies with Therapeutic Activity against Chikungunya Virus. Cell Host Microbe 18:86-95|
|Pulendran, Bali (2015) The varieties of immunological experience: of pathogens, stress, and dendritic cells. Annu Rev Immunol 33:563-606|
|Price, Aryn A; Sampson, Timothy R; Ratner, Hannah K et al. (2015) Cas9-mediated targeting of viral RNA in eukaryotic cells. Proc Natl Acad Sci U S A 112:6164-9|
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