Cross-reactive dengue immune complexes modulate innate antiviral responses to Zika virus infection in human placental macrophages

Abstract

Abstract Zika virus (ZIKV) is a mosquito-borne flavivirus that has recently emerged in the Americas and is a pathogen of significant public health concern. Unique amongst flaviviruses, ZIKV can be vertically transmitted from an infected mother to the developing fetus in utero, in some cases resulting in adverse pregnancy outcomes, including spontaneous abortion and fetal brain abnormalities. We recently found that Hofbauer cells (HCs), a fetal-derived placental macrophage, are primary targets for ZIKV infection. Further, cross-reactive dengue antibodies facilitate ZIKV transcytosis across the placental barrier to seed infection within HCs. However, little is known about the innate immune mechanisms of HCs to limit virus replication and spread within the placenta. Here, we report that HCs express the RIG-I-like receptors, RIG-I, MDA5, and LGP2, and the cytosolic DNA sensor, cGAS, and can induce a potent innate immune response characterized by production of monocyte and macrophage chemoattractants, MCP-1, MIP-1α, and MIP-1β. In contrast, HCs infected in the presence or absence of ZIKV immune complexes induced little to no type I interferon (IFN), pro-inflammatory cytokines, or chemokines. Notably, HCs infected with ZIKV immune complexes displayed reduced antiviral gene induction as compared to HCs infected in the absence of immune complexes despite similar kinetics of virus replication. We are currently performing RNA sequencing analyses to determine how binding of viral immune complexes can alter the antiviral gene signature within HCs to enhance productive ZIKV infection. These studies will further our understanding of innate immunologic mechanisms and modulation during vertical transmission of flaviviruses in the placenta.