Teglas Timea, Torices Silvia, Marcos Anne Caroline, Orzechowska-Wylęgała Bogusława, Toborek Michal
Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Suite 528, 1011 NW 15th Street, Miami, FL, 33136, USA.
Department of Pediatric Otolaryngology and Surgery of Head and Neck, Medical University of Silesia, Katowice, Poland.
Fluids Barriers CNS. 2025 Jun 16;22(1):57. doi: 10.1186/s12987-025-00669-2.
Zika virus (ZIKV) is a mosquito-borne Flavivirus with a strong affinity for the central nervous system (CNS). After infection, ZIKV can cross the blood-brain barrier (BBB) and reach the CNS, causing potential harm to both adult and developing brains.
The current study aims to evaluate how dysregulated circadian rhythms can affect brain infection by ZIKV, as biorhythms regulate essential physiological processes and disrupted circadian clock can contribute to the pathogenesis of multiple disorders. Both ZIKV infection and circadian rhythm alterations have been related to the disruption of the BBB integrity by modulating the expression of the tight junction (TJ) proteins, however, the input of circadian misalignment on ZIKV infection has never been studied in the literature.
Infection of brain endothelial cells with ZIKV selectively impacted endothelial permeability and dysregulated the expression of TJ and mitochondrial proteins. Importantly, these effects were potentiated by silencing Bmal1, a critical circadian rhythm gene. These results were then confirmed in vivo in Bmal1 endothelial cell-specific knockout mice, which were infected with ZIKV at 10 PFU (plaque-forming unit) by retro-orbital infusion. ZIKV infection resulted in a marked decrease in claudin-5, occludin, JAM-3, and ZO-1 expression levels in these mice. In addition, ZIKV affected the expression of FIS1 protein levels and the respiratory complexes of II, III, and IV in mice lacking Bmal1 expression in endothelial cells.
Findings from this study contribute to a better understanding of the impact of circadian misalignment on the pathology of ZIKV infection in the adult brain.
寨卡病毒（ZIKV）是一种通过蚊子传播的黄病毒，对中枢神经系统（CNS）具有很强的亲和力。感染后，ZIKV可穿过血脑屏障（BBB）并到达中枢神经系统，对成体和发育中的大脑均造成潜在损害。
当前研究旨在评估昼夜节律失调如何影响ZIKV对大脑的感染，因为生物节律调节基本生理过程，而昼夜节律紊乱会导致多种疾病的发病机制。ZIKV感染和昼夜节律改变均与通过调节紧密连接（TJ）蛋白的表达破坏血脑屏障完整性有关，然而，昼夜节律失调对ZIKV感染的影响在文献中从未被研究过。
用ZIKV感染脑内皮细胞会选择性地影响内皮通透性，并使TJ和线粒体蛋白的表达失调。重要的是，通过沉默关键的昼夜节律基因Bmal1可增强这些作用。然后在Bmal1内皮细胞特异性敲除小鼠体内证实了这些结果，这些小鼠通过眶后注射以10个蚀斑形成单位（PFU）感染ZIKV。ZIKV感染导致这些小鼠中闭合蛋白-5、闭锁蛋白、连接黏附分子-3和紧密连接蛋白-1的表达水平显著降低。此外，ZIKV影响了在内皮细胞中缺乏Bmal1表达的小鼠中FIS1蛋白水平以及呼吸复合体II、III和IV的表达。
本研究结果有助于更好地理解昼夜节律失调对成体大脑中ZIKV感染病理学的影响。
