Flaviviruses are a group of positive-stranded RNA viruses that have a global impact on public health due to their widespread distribution and ability to cause severe disease in humans. Several viruses in this genus, such as dengue and West Nile viruses (DENV and WNV, respectively), are considered emerging or re-emerging pathogens due to significant increases in morbidity and mortality observed during the past decade. Each year, 50-100 million individuals are infected by one of the four serotypes of DENV, resulting in roughly 250,000 cases of a severe and potentially fatal hemorrhagic manifestation of the disease. WNV is an encephalitic flavivirus introduced into North America in 1999 that has subsequently spread across the continent resulting in more than 29,000 reported clinical cases and approximately 1,100 fatalities (www.cdc.gov). While the clinical burden of WNV appears modest by comparison to other viral infectious diseases, long-term studies of morbidity in individuals that survive acute WNV infection suggest the true clinical burden of WNV disease in North America may not yet be realized. Humoral immunity is a critical aspect of host protection against flaviviruses;eliciting protective antibodies is a primary focus of ongoing vaccine development efforts for several of these viruses, including WNV and DENV. Complicating these efforts is the potential for antibodies elicited by natural infection or vaccination to modulate DENV pathogenesis and enhance disease. Antibody-dependent enhancement of infection (ADE) describes a dramatic increase in the infection of Fc-gamma-receptor-bearing cells in the presence of sub-neutralizing concentrations of antibody or immune sera. The biochemical and functional properties of a protective antibody response are not known. A primary goal of the Viral Pathogenesis Section is to understand the mechanisms of humoral immunity against flaviviruses. We are investigating the molecular and structural basis of antibody-mediated neutralization and enhancement of flavivirus infection, while working to apply the knowledge and perspectives arising from these studies toward dissecting the functional properties of the polyclonal antibody response of naturally infected and vaccinated humans.

Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2013
Total Cost
$770,606
Indirect Cost
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State
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Dowd, Kimberly A; Mukherjee, Swati; Kuhn, Richard J et al. (2014) Combined effects of the structural heterogeneity and dynamics of flaviviruses on antibody recognition. J Virol :
Mukherjee, Swati; Pierson, Theodore C; Dowd, Kimberly A (2014) Pseudo-infectious reporter virus particles for measuring antibody-mediated neutralization and enhancement of dengue virus infection. Methods Mol Biol 1138:75-97
Edeling, Melissa A; Austin, S Kyle; Shrestha, Bimmi et al. (2014) Potent dengue virus neutralization by a therapeutic antibody with low monovalent affinity requires bivalent engagement. PLoS Pathog 10:e1004072
Mukherjee, Swati; Dowd, Kimberly A; Manhart, Carolyn J et al. (2014) Mechanism and significance of cell type-dependent neutralization of flaviviruses. J Virol 88:7210-20
Obara, Christopher J; Dowd, Kimberly A; Ledgerwood, Julie E et al. (2013) Impact of viral attachment factor expression on antibody-mediated neutralization of flaviviruses. Virology 437:20-7
Sukupolvi-Petty, Soila; Brien, James D; Austin, S Kyle et al. (2013) Functional analysis of antibodies against dengue virus type 4 reveals strain-dependent epitope exposure that impacts neutralization and protection. J Virol 87:8826-42
Sashihara, Junji; Burbelo, Peter D; Savoldo, Barbara et al. (2009) Human antibody titers to Epstein-Barr Virus (EBV) gp350 correlate with neutralization of infectivity better than antibody titers to EBV gp42 using a rapid flow cytometry-based EBV neutralization assay. Virology 391:249-56
Vogt, Matthew R; Moesker, Bastiaan; Goudsmit, Jaap et al. (2009) Human monoclonal antibodies against West Nile virus induced by natural infection neutralize at a postattachment step. J Virol 83:6494-507