Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Brain Behav Immun. 2024 May;118:318-333. doi: 10.1016/j.bbi.2024.02.035. Epub 2024 Mar 7.
Zika virus (ZIKV), the causative agent of Zika fever, is a flavivirus transmitted by mosquitoes of the Aedes genus. Zika virus infection has become an international concern due to its association with severe neurological complications such as fetal microcephaly. Viral infection can induce the release of ATP in the extracellular environment, activating receptors sensitized by extracellular nucleotides, such as the P2X7 receptor. This receptor is the primary purinergic receptor involved in neuroinflammation, neurodegeneration, and immunity. In this work, we investigated the role of ATP-P2X7 receptor signaling in Zika-related brain abnormalities. Wild-type mice (WT) and P2X7 receptor-deficient (P2X7) C57BL/6 newborn mice were subcutaneously inoculated with 5 × 10plaque-forming units of ZIKV or mock solution. P2X7 receptor expression increased in the brain of Zika virus-infected mice compared to the mock group. Comparative analyses of the hippocampi from WT and P2X7mice revealed that the P2X7 receptor increased hippocampal damage in CA1/CA2 and CA3 regions. Doublecortin expression decreased significantly in the brains of ZIKV-infected mice. WT ZIKV-infected mice showed impaired motor performance compared to P2X7 infected mice. WT ZIKV-infected animals showed increased expression of glial markers GFAP (astrocytes) and IBA-1 (microglia) compared to P2X7 infected mice. Although the P2X7 receptor contributes to neuronal loss and neuroinflammation, WT mice were more efficient in controlling the viral load in the brain than P2X7 receptor-deficient mice. This result was associated with higher induction of TNF-α, IFN-β, and increased interferon-stimulated gene expression in WT mice than P2X7ZIKV-infected. Finally, we found that the P2X7 receptor contributes to inhibiting the neuroprotective signaling pathway AKT/mTOR while stimulating the caspase-3 activation, possibly two distinct pathways contributing to neurodegeneration. These findings suggest that ATP-P2X7 receptor signaling contributes to the antiviral response in the brain of ZIKV-infected mice while increasing neuronal loss, neuroinflammation, and related brain abnormalities.
寨卡病毒（ZIKV）是寨卡热的病原体，是一种通过伊蚊属传播的黄病毒。寨卡病毒感染由于与胎儿小头畸形等严重神经并发症有关而引起国际关注。病毒感染可诱导细胞外环境中 ATP 的释放，激活细胞外核苷酸敏化的受体，如 P2X7 受体。该受体是参与神经炎症、神经退行性变和免疫的主要嘌呤能受体。在这项工作中，我们研究了 ATP-P2X7 受体信号在寨卡病毒相关脑异常中的作用。野生型（WT）和 P2X7 受体缺陷型（P2X7）C57BL/6 新生小鼠皮下接种 5×10plaque 形成单位的寨卡病毒或模拟溶液。与模拟组相比，寨卡病毒感染小鼠脑中的 P2X7 受体表达增加。WT 和 P2X7 小鼠海马的比较分析表明，P2X7 受体增加了 CA1/CA2 和 CA3 区的海马损伤。双皮质蛋白在寨卡病毒感染小鼠脑中的表达显著降低。与 P2X7 感染小鼠相比，WT 寨卡病毒感染小鼠的运动表现受损。与 P2X7 感染小鼠相比，WT 寨卡病毒感染动物的神经胶质标志物 GFAP（星形胶质细胞）和 IBA-1（小胶质细胞）表达增加。尽管 P2X7 受体有助于神经元丢失和神经炎症，但 WT 小鼠比 P2X7 受体缺陷型小鼠更有效地控制大脑中的病毒载量。这一结果与 WT 小鼠中 TNF-α、IFN-β 的诱导更高以及 IFN 刺激基因表达增加有关，而 P2X7ZIKV 感染则相反。最后，我们发现 P2X7 受体有助于抑制 AKT/mTOR 神经保护信号通路，同时刺激 caspase-3 激活，这可能是两种不同的通路导致神经退行性变。这些发现表明，ATP-P2X7 受体信号有助于寨卡病毒感染小鼠的抗病毒反应，同时增加神经元丢失、神经炎症和相关脑异常。
