Abstract
Dengue virus (DENV) is a prevalent human pathogen, infecting approximately 400 million individuals per year and causing symptomatic disease in approximately 100 million. A distinct feature of dengue is the increased risk for severe disease in some individuals with preexisting DENV-specific immunity. One proposed mechanism for this phenomenon is antibody-dependent enhancement (ADE), in which poorly-neutralizing IgG antibodies from a prior infection opsonize DENV to increase infection of Fc gamma receptor-bearing cells. While IgM and IgG are the most commonly studied DENV-reactive antibody isotypes, our group and others have described the induction of DENV-specific serum IgA responses during dengue. We hypothesized that monomeric IgA would be able to neutralize DENV without the possibility of ADE. To test this, we synthesized IgG and IgA versions of two different DENV-reactive monoclonal antibodies. We demonstrate that isotype-switching does not affect the antigen binding and neutralization properties of the two mAbs. We show that DENV-reactive IgG, but not IgA, mediates ADE in Fc gamma receptor-positive K562 cells. Furthermore, we show that IgA potently antagonizes the ADE activity of IgG. These results suggest that levels of DENV-reactive IgA induced by DENV infection might regulate the overall IgG mediated ADE activity of DENV-immune plasma in vivo, and may serve as a predictor of disease risk.
Highlights
Dengue virus (DENV) is one of the most widespread vector-borne viral pathogens in the world
In this study we demonstrate that DENV-reactive IgA monoclonal antibodies can bind and neutralize DENV but are incapable of facilitating antibody-dependent enhancement (ADE) of DENV infection in vitro
The presence of DENV-reactive IgA can significant blunt the DENVinfection enhancing activity of both DENV-reactive monoclonal IgG and polyclonal DENV-immune serum in a completive fashion. These results suggest an unappreciated role for DENV-reactive IgA during the humoral response to DENV infection and raise the potential that IgA could act as either a natural or therapeutic regulator of DENV dissemination and infection-attendant inflammation
Summary
Dengue virus (DENV) is one of the most widespread vector-borne viral pathogens in the world. DENV and its mosquito vectors can currently be found across Central and South America, South and South-East Asia, the Western Pacific, and sub-Saharan Africa, meaning 40% of the world’s population is currently at risk of exposure and infection [1,2,3]. A distinct epidemiological feature of dengue as compared to other flaviviral diseases is the increased risk for severe disease upon heterologous secondary infection [8]. While the risk factors associated with developing severe dengue upon secondary DENV exposure are complex and incompletely understood, the leading mechanistic explanation for this phenomenon is a process known as antibody-dependent enhancement (ADE) [9, 10]. In-vitro assessments of serum ADE activity in DENVprimed non-human primates have been shown to correlate with viral titers following heterologous attenuated DENV infection [19]
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