Cross-reactive antibodies facilitate innate sensing of dengue and Zika viruses

The Aedes aegypti mosquito transmits both dengue virus (DENV) and Zika virus (ZIKV) . Individuals in endemic areas are at risk for infection with both viruses, as well as for repeated DENV infection. In the presence of anti-DENV antibodies, outcomes of secondary DENV infection range from mild to life threatening. Furthermore, the role of cross-reactive antibodies on the course of ZIKV infection remains unclear. We assessed the ability of cross-reactive DENV mAbs or polyclonal immunoglobulin isolated after DENV vaccination to upregulate type I IFN production by plasmacytoid DCs (pDCs) in response to both heterotypic DENV- and ZIKV-infected cells. We found a range in the ability of antibodies to increase pDC IFN production and a positive correlation between IFN production and the ability of an antibody to bind to the infected cell surface. Engagement of Fc receptors on the pDC and engagement of epitope on the infected cell by the Fab portion of the same antibody molecule was required to mediate increased IFN production by providing specificity to and promoting pDC sensing of DENV or ZIKV. This represents a mechanism independent of neutralization by which preexisting cross-reactive DENV antibodies could protect a subset of individuals from severe outcomes during secondary heterotypic DENV or ZIKV infection.