Zika virus (ZIKV) has been associated with several neurological complications in adult patients. We used a mouse model deficient in TRIF and IPS-1 adaptor proteins, which are involved in type I interferon production, to study the role of microglia during brain infection by ZIKV. Young adult mice were infected intravenously with the contemporary ZIKV strain PRVABC59 (1 × 105 PFUs/100 µL). Infected mice did not present overt clinical signs of the disease nor body weight loss compared with noninfected animals. However, mice exhibited a viremia and a brain viral load that were maximal (1.3 × 105 genome copies/mL and 9.8 × 107 genome copies/g of brain) on days 3 and 7 post-infection (p.i.), respectively. Immunohistochemistry analysis showed that ZIKV antigens were distributed in several regions of the brain, especially the dorsal hippocampus. The number of Iba1+/TMEM119+ microglia remained similar in infected versus noninfected mice, but their cell body and arborization areas significantly increased in the stratum radiatum and stratum lacunosum-moleculare layers of the dorsal hippocampus cornu ammoni (CA)1, indicating a reactive state. Ultrastructural analyses also revealed that microglia displayed increased phagocytic activities and extracellular digestion of degraded elements during infection. Mice pharmacologically depleted in microglia with PLX5622 presented a higher brain viral load compared to untreated group (2.8 × 1010 versus 8.5 × 108 genome copies/g of brain on day 10 p.i.) as well as an increased number of ZIKV antigens labeled with immunogold in the cytoplasm and endoplasmic reticulum of neurons and astrocytes indicating an enhanced viral replication. Furthermore, endosomes of astrocytes contained nanogold particles together with digested materials, suggesting a compensatory phagocytic activity upon microglial depletion. These results indicate that microglia are involved in the control of ZIKV replication and/or its elimination in the brain. After depletion of microglia, the removal of ZIKV-infected cells by phagocytosis could be partly compensated by astrocytes.

中文翻译：

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在年轻的成年免疫缺陷小鼠寨卡病毒脑炎期间，小胶质细胞参与吞噬作用和细胞外消化

寨卡病毒 (ZIKV) 与成年患者的几种神经系统并发症有关。我们使用了一个缺乏 TRIF 和 IPS-1 衔接蛋白的小鼠模型，这些蛋白与 I 型干扰素的产生有关，以研究小胶质细胞在 ZIKV 脑感染过程中的作用。用当代 ZIKV 菌株 PRVABC59 (1 × 105 PFUs/100 µL) 静脉内感染年轻成年小鼠。与未感染的动物相比，感染的小鼠没有出现明显的疾病临床症状，也没有体重减轻。然而，小鼠在感染后第 3 天和第 7 天（pi）分别表现出最大的病毒血症和脑病毒载量（1.3 × 105 基因组拷贝/mL 和 9.8 × 107 基因组拷贝/g 脑）。免疫组织化学分析表明，ZIKV 抗原分布在大脑的多个区域，尤其是背侧海马区。Iba1+/TMEM119+ 小胶质细胞的数量在感染小鼠和未感染小鼠中保持相似，但它们的细胞体和树枝状区域在背侧海马角氨 (CA)1 的辐射层和腔隙分子层中显着增加，表明处于反应状态。超微结构分析还显示，小胶质细胞在感染期间表现出增强的吞噬活性和降解元素的细胞外消化。与未治疗组相比，用 PLX5622 药理学耗尽小胶质细胞的小鼠脑病毒载量更高（感染后第 10 天 2.8 × 1010 对 8.5 × 108 基因组拷贝/g 脑），并且免疫金标记的 ZIKV 抗原数量增加神经元和星形胶质细胞的细胞质和内质网表明病毒复制增强。此外，星形胶质细胞的内体含有纳米金颗粒和消化的物质，表明小胶质细胞耗竭后具有补偿性吞噬活性。这些结果表明，小胶质细胞参与控制 ZIKV 复制和/或其在大脑中的消除。在小胶质细胞耗尽后，星形胶质细胞可以部分补偿通过吞噬作用去除 ZIKV 感染的细胞。