Respiratory infection with SARS-CoV-2 causes systemic vascular inflammation and cognitive impairment. We sought to identify the underlying mechanisms mediating cerebrovascular dysfunction and inflammation following mild respiratory SARS-CoV-2 infection. To this end, we conduced unbiased transcriptional analysis to identify brain endothelial cell signaling pathways dysregulated by mouse adapted SARS-CoV-2 MA10 in aged immunocompetent C57Bl/6 mice in vivo. This analysis revealed significant suppression of Wnt/β-catenin signaling, a critical regulator of blood-brain barrier (BBB) integrity. We therefore hypothesized that enhancing cerebrovascular Wnt/β-catenin activity would offer protection against BBB permeability, neuroinflammation, and neurological signs in acute infection. Indeed, we found that delivery of cerebrovascular-targeted, engineered Wnt7a ligands protected BBB integrity, reduced T cell infiltration of the brain, and reduced microglial activation in SARS-CoV-2 infection. Importantly, this strategy also mitigated SARS-CoV-2 induced deficits in the novel object recognition assay for learning and memory and the pole descent task for bradykinesia. These observations suggest that enhancement of Wnt/β-catenin signaling or its downstream effectors could be potential interventional strategies for restoring cognitive health following viral infections.

中文翻译：

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工程化 Wnt7a 配体可挽救 COVID-19 小鼠模型中的血脑屏障和认知缺陷

SARS-CoV-2 呼吸道感染会导致全身血管炎症和认知障碍。我们试图确定轻度呼吸道 SARS-CoV-2 感染后介导脑血管功能障碍和炎症的潜在机制。为此，我们进行了无偏见的转录分析，以识别老年免疫功能正常的 C57Bl/6 小鼠体内因小鼠适应性 SARS-CoV-2 MA10 失调而失调的脑内皮细胞信号传导通路。该分析揭示了 Wnt/β-catenin 信号传导的显着抑制，Wnt/β-catenin 信号传导是血脑屏障 (BBB) 完整性的关键调节因子。因此，我们假设增强脑血管 Wnt/β-catenin 活性可以针对急性感染中的 BBB 通透性、神经炎症和神经系统体征提供保护。事实上，我们发现，递送针对脑血管的工程 Wnt7a 配体可以保护 BBB 完整性，减少 T 细胞对大脑的浸润，并减少 SARS-CoV-2 感染中小胶质细胞的激活。重要的是，这一策略还减轻了 SARS-CoV-2 引起的学习和记忆新物体识别测定以及运动迟缓的极地下降任务中的缺陷。这些观察结果表明，增强 Wnt/β-连环蛋白信号或其下游效应器可能是恢复病毒感染后认知健康的潜在干预策略。