Krishna Venkatramana D, Chang Allison, Korthas Holly, Var Susanna R, Low Walter C, Li Ling, Cheeran Maxim C-J
Department of Veterinary Population Medicine, University of Minnesota, Saint Paul, MN 55108, USA.
Graduate Program in Neuroscience.
bioRxiv. 2023 Aug 14:2023.08.11.552998. doi: 10.1101/2023.08.11.552998.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent for the worldwide COVID-19 pandemic, is known to infect people of all ages and both sexes. Senior populations have the greatest risk of severe disease, and sexual dimorphism in clinical outcomes has been reported in COVID-19. SARS-CoV-2 infection in humans can cause damage to multiple organ systems, including the brain. Neurological symptoms are widely observed in patients with COVID-19, with many survivors suffering from persistent neurological and cognitive impairment, potentially accelerating Alzheimer's disease. 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/6 mice were inoculated, by intranasal route, with SARS-CoV-2 lineage B.1.351 variant known to infect mice. Older animals and in particular males exhibited a significantly greater weight loss starting at 4 dpi. In addition, male animals exhibited higher viral RNA loads and higher titers of infectious virus in the lung, which was particularly evident in males at 16 months of age. Notably, no viral RNA was detected in the brains of infected mice, regardless of age or sex. Nevertheless, expression of IL-6, TNF-α, and CCL-2 in the lung and brain was increased with viral infection. An unbiased brain RNA-seq/transcriptomic analysis showed that SARS-CoV-2 infection caused significant changes in gene expression profiles in the brain, with innate immunity, defense response to virus, cerebravascular and neuronal functions, as the major molecular networks affected. The data presented in this study show that SARS-CoV-2 infection triggers a neuroinflammatory response despite the lack of detectable virus in the brain. Age and sex have a modifying effect on this pathogenic process. Aberrant activation of innate immune response, disruption of blood-brain barrier and endothelial cell integrity, and supression 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）是全球新冠肺炎大流行的病原体，已知可感染各年龄段和性别的人群。老年人群患重症的风险最大，且新冠肺炎的临床结局存在性别差异。人类感染SARS-CoV-2可导致多个器官系统受损，包括大脑。新冠肺炎患者中广泛观察到神经症状，许多幸存者患有持续性神经和认知障碍，这可能会加速阿尔茨海默病的发展。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。通过鼻内途径给野生型C57BL/6小鼠接种已知可感染小鼠的SARS-CoV-2 B.1.351谱系变体。从感染后第4天开始，老年动物尤其是雄性动物体重显著下降。此外，雄性动物肺部的病毒RNA载量更高，传染性病毒滴度也更高，这在16月龄的雄性动物中尤为明显。值得注意的是，无论年龄或性别，在感染小鼠的大脑中均未检测到病毒RNA。然而，病毒感染会使肺和脑中白细胞介素-6、肿瘤坏死因子-α和CCL-2的表达增加。一项无偏倚的脑RNA测序/转录组分析表明，SARS-CoV-2感染导致大脑基因表达谱发生显著变化，主要受影响的分子网络包括固有免疫、对病毒的防御反应、脑血管和神经元功能。本研究提供的数据表明，尽管在大脑中未检测到可检测的病毒，但SARS-CoV-2感染仍会引发神经炎症反应。年龄和性别对这一致病过程具有调节作用。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感染对大脑产生影响的基础。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，以缓解新冠肺炎期间观察到的神经功能障碍。
