DENV-specific IgA contributes protective and non-pathologic function during antibody-dependent enhancement of DENV infection

Dengue represents a growing public health burden worldwide, accounting for approximately 100 million symptomatic cases and tens of thousands of fatalities yearly. Prior infection with one serotype of dengue virus (DENV) is the greatest known risk factor for severe disease upon secondary infection with a heterologous serotype, a risk which increases as serotypes co-circulate in endemic regions. This disease risk is thought to be mediated by IgG-isotype antibodies raised during a primary infection, which poorly neutralize heterologous DENV serotypes and instead opsonize virions for uptake by FcγR-bearing cells. This antibody-dependent enhancement (ADE) of infection leads to a larger proportion of susceptible cells infected, higher viremia and greater immunopathology. We have previously characterized the induction of a serum IgA response, along with the typical IgM and IgG responses, during dengue infection, and have shown that DENV-reactive IgA can neutralize DENV and competitively antagonize IgG-mediated ADE. Here, we evaluate the potential for IgA itself to cause ADE. We show that IgG, but not IgA, mediated ADE of infection in cells expressing both FcαR and FcγRs. IgG-mediated ADE stimulated significantly higher pro-inflammatory cytokine production by primary human macrophages, while IgA did not affect, or slightly suppressed, this production. Mechanistically, we show that DENV/IgG immune complexes bind susceptible cells significantly more efficiently than DENV/IgA complexes or virus alone. Finally, we show that over the course of primary dengue infection, the expression of FcγRI (CD64) increases during the period of acute viremia, while FcγRIIa (CD32) and FcαR (CD89) expression decreases, thereby further limiting the ability of IgA to facilitate ADE in the presence of DENV. Overall, these data illustrate the distinct protective role of IgA during ADE of dengue infection and highlight the potential therapeutic and prognostic value of DENV-specific IgA.