The IRE1/XBP1s Axis Regulates Innate Immune Responses in Conventional Dendritic Cells During ZIKV Infection

Abstract

Zika virus (ZIKV) is a mosquito-borne flavivirus causing a major epidemic in the Americas in 2015. Dendritic cells (DCs) are leukocytes with key antiviral functions, but their role in ZIKV infection remains under investigation. While most studies have focused on the monocyte-derived subtype of DCs, less is known about conventional dendritic cells (cDCs), essential for the orchestration of antiviral adaptive immunity. This study investigates the mechanisms by which cDCs respond to ZIKV for antiviral cytokine production. Here, using murine cultures, we demonstrate that ZIKV infection and not detection of ZIKV-infected dead cells activates cDCs by inducing type I interferons (IFN-I) and proinflammatory cytokines. Furthermore, ZIKV-infected cDCs markedly activated the IRE1/XBP1s axis of the unfolded protein response (UPR). Flow cytometry analysis indicates that among cDCs, type 1 cDCs (cDC1s) are responsible for ZIKV detection. Functionally, genetic loss of XBP1s curtailed expression of the costimulatory molecule CD86 and the production of IFN-I and proinflammatory cytokines by cDCs, without exhibiting increased susceptibility to ZIKV infection. These effects are attributable to perturbations in the IRE1/XBP1s axis and not due to overcompensation of PERK or IRE1 kinase signaling. Finally, tissue resident cDCs also exhibit susceptibility to infection, potentially establishing these cells as ZIKV targets in vivo. These findings underscore a critical role for the IRE1/XBP1s pathway in fine-tuning cDC activation to ZIKV, linking viral recognition to cDC functional maturation and opening new avenues for exploring UPR pathways targeting cDCs in the context of flavivirus infections.