Guzmán-Rodríguez Mónica, Hernández-Díaz Tomás, Lisboa Paula, López-Schettini Javier, Sanhueza Sofia, Leyton Lisette, Iwawaki Takao, Soto-Rifo Ricardo, Osorio Fabiola
Immunology Program, Laboratory of Immunology and Cellular Stress, Faculty of Medicine, Institute of Biomedical Sciences, Universidad de Chile, Santiago, Chile.
Virology Program, Laboratory of Molecular and Cellular Virology, Faculty of Medicine, Institute of Biomedical Sciences, Universidad de Chile, Santiago, Chile.
FASEB J. 2025 Sep 15;39(17):e71025. doi: 10.1096/fj.202501186R.
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.
寨卡病毒（ZIKV）是一种通过蚊子传播的黄病毒，于2015年在美洲引发了一场大规模疫情。树突状细胞（DCs）是具有关键抗病毒功能的白细胞，但其在寨卡病毒感染中的作用仍在研究之中。虽然大多数研究集中在单核细胞来源的DCs亚型上，但对于协调抗病毒适应性免疫至关重要的传统树突状细胞（cDCs）却知之甚少。本研究探讨了cDCs对寨卡病毒产生抗病毒细胞因子的反应机制。在此，我们利用小鼠培养物证明，是寨卡病毒感染而非对寨卡病毒感染死亡细胞的检测通过诱导I型干扰素（IFN-I）和促炎细胞因子激活了cDCs。此外，寨卡病毒感染的cDCs显著激活了未折叠蛋白反应（UPR）的IRE1/XBP1s轴。流式细胞术分析表明，在cDCs中，1型cDCs（cDC1s）负责检测寨卡病毒。在功能上，XBP1s的基因缺失减少了共刺激分子CD86的表达以及cDCs产生的IFN-I和促炎细胞因子，且未表现出对寨卡病毒感染的易感性增加。这些效应归因于IRE1/XBP1s轴的扰动，而非PERK或IRE1激酶信号的过度补偿。最后，组织驻留cDCs也表现出对感染的易感性，这可能使这些细胞成为体内寨卡病毒的靶标。这些发现强调了IRE1/XBP1s途径在微调cDCs对寨卡病毒的激活中的关键作用，将病毒识别与cDCs功能成熟联系起来，并为在黄病毒感染背景下探索靶向cDCs的UPR途径开辟了新途径。
