Krishna Venkatramana D, Chang Allison, Korthas Holly, Var Susanna R, Seelig Davis M, Low Walter C, Li Ling, Cheeran Maxim C-J
Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, United States.
Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, United States.
Front Microbiol. 2024 Jul 15;15:1404312. doi: 10.3389/fmicb.2024.1404312. eCollection 2024.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, is known to infect people of all ages and both sexes. Senior populations have the greatest risk of severe COVID-19, and sexual dimorphism in clinical outcomes has been reported. Neurological symptoms are widely observed in COVID-19 patients, with many survivors exhibiting persistent neurological and cognitive impairment. The present study aims to investigate the impact of age and sex on the neuroinflammatory response to SARS-CoV-2 infection using a mouse model. Wild-type C57BL/6J mice were intranasally inoculated with SARS-CoV-2 lineage B.1.351, a variant known to infect mice. Older male mice exhibited a significantly greater weight loss and higher viral loads in the lung at 3 days post infection. Notably, no viral RNA was detected in the brains of infected mice. Nevertheless, expression of IL-6, TNF-α, and CCL-2 in the lung and brain increased with viral infection. RNA-seq transcriptomic analysis of brains showed that SARS-CoV-2 infection caused significant changes in gene expression profiles, implicating innate immunity, defense response to virus, and cerebrovascular and neuronal functions. These findings demonstrate that SARS-CoV-2 infection triggers a neuroinflammatory response, despite the lack of detectable virus in the brain. Aberrant activation of innate immune response, disruption of blood-brain barrier and endothelial cell integrity, and suppression of neuronal activity and axonogenesis underlie the impact of SARS-CoV-2 infection on the brain. Understanding the role of these affected pathways in SARS-CoV-2 pathogenesis helps identify appropriate points of therapeutic interventions to alleviate neurological dysfunction observed during COVID-19.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是新冠病毒病（COVID-19）的病原体，已知可感染所有年龄段和性别的人群。老年人群感染COVID-19后出现重症的风险最高，并且已有关于临床结局存在性别差异的报道。COVID-19患者中广泛观察到神经症状，许多幸存者表现出持续的神经和认知障碍。本研究旨在使用小鼠模型研究年龄和性别对SARS-CoV-2感染所致神经炎症反应的影响。将野生型C57BL/6J小鼠经鼻接种SARS-CoV-2 B.1.351谱系毒株，该毒株是一种已知可感染小鼠的变体。感染后3天，老年雄性小鼠体重减轻显著更明显，肺内病毒载量更高。值得注意的是，在感染小鼠的脑中未检测到病毒RNA。尽管如此，肺和脑中白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）和趋化因子配体2（CCL-2）的表达随病毒感染而增加。对脑进行的RNA测序转录组分析表明，SARS-CoV-2感染导致基因表达谱发生显著变化，涉及固有免疫、对病毒的防御反应以及脑血管和神经元功能。这些发现表明，尽管在脑中未检测到可检出的病毒，但SARS-CoV-2感染仍会引发神经炎症反应。固有免疫反应的异常激活、血脑屏障和内皮细胞完整性的破坏以及神经元活动和轴突发生的抑制是SARS-CoV-2感染对脑产生影响的基础。了解这些受影响途径在SARS-CoV-2发病机制中的作用有助于确定合适的治疗干预点，以减轻COVID-19期间观察到的神经功能障碍。
