Impact of Zika Virus on Human Dendritic Cells
Abstract: Zika virus (ZIKV) is a mosquito-borne flavivirus, transmitted to humans by Aedes aegypti and Aedes albopictus mosquitos, and has also more recently been shown to transmit from human-to-human sexually and vertically from mother to fetus. ZIKV infection, typically causing mild clinical symptoms, has been linked to a range of neurological complications including microcephaly in fetuses and Guillain-barré syndrome in adults. ZIKV’s recent emergence poses a public health emergency, and new pathological information is required for developing effective interventions to ameliorate the burden of disease. The dendritic cell (DC), the key innate immune responder that ultimately drives anti-viral adaptive immunity, has known interactions with ZIKV. However, the nature and outcomes of this interaction, and its role in ZIKV pathology needs further elucidation. Here we hypothesize ZIKV can infect and modify the phenotype and function of dendritic cells, which influences the nature of their subsequent interplay with pre-existing ZIKV-Ag responsive memory T cells. We found that ZIKV can indeed infect both immature and mature DCs, and that DCs can transfer infection to bystander cells. We also found that exposure of DCs to ZIKV alters their function, maturation status, and survival. Interestingly, we note that the capacity of ZIKV to infect DCs is greatly influenced by the environmental signals received by DCs during their maturation process, and that type-1 polarized DC are inherently more resistant than type-2 matured DC. Importantly, when activated by the CD4+ T cell helper signal CD40L, ZIKV infected DC proved to be more resistant to ZIKV-induced cell death. And finally, on the background of dengue virus immunity, we found that dengue antigen specific memory T cells can dysfunctionally cross-react with ZIKV antigen presented by DC, leading to enhanced DC activation rather than elimination. These findings contribute to our understanding of basic ZIKV : DC interactions, and may help to provide a better understanding of ZIKV pathogenesis leading towards the development of effective interventions to protect and treat those who may become exposed to ZIKV.
Advisor: Dr. Robbie Mailliard