Wu Ziyan, Xu Honglin, Fan Siyuan, Feng Futai, Li Zhan, Cheng Linlin, Li Haolong, Liu Yongmei, Zhan Haoting, Feng Xinxin, Wang Siyu, Zhang Shulan, Li Yongzhe
Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Shuaifuyuan Hutong, Dongcheng District, Beijing, 100730, China.
Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Virol J. 2025 Apr 28;22(1):123. doi: 10.1186/s12985-025-02754-2.
A mendelian randomization (MR) analysis was conducted to investigate whether SARS-CoV-2 invaded the human nervous system. This was confirmed by an increase in biomarkers found in the cerebrospinal fluid (CSF) and plasma of COVID-19 patients. To confirm the neuroinvasive properties of SARS-CoV-2, a series of analyses were conducted utilizing accessible datasets by MR. In addition, external validation was conducted by testing specific proteins in a retrospective cohort study, which included 40 COVID-19 patients with neurological complications and 15 disease controls (DC). Our investigation revealed the hospitalization, severity of COVID-19 increased the area and volume of certain brain regions, but no other significant causal effects were found of brain imaging-derived phenotypes (IDPs) on COVID-19. Notably, the COVID-19 hospitalization significantly increased the area and volume of the left caudal middle frontal gyrus (p_fdr = 0.012; p_fdr = 0.012, respectively). Additionally, COVID-19 severity was linked to the area, volume of the right caudal anterior-cingulate cortex and the volume of the right cuneus cortex (p_fdr = 0.023; p_fdr = 0.025; p_fdr = 0.026, respectively). In the CSF of COVID-19 patients, the median level of CHI3L1 was significantly higher (13677 pg/mL) compared to the DC group (8421 pg/mL, p < 1.00E-04). Similar trends were also found in CSF KLK6 and NGF-β. Additionally, the median NRGN level in plasma was significantly higher in the COVID-19 group (1013.00 pg/mL) compared to the control group (360.00 pg/mL, p = 6.50E-03). A subgroup analysis demonstrated that COVID-19 patients experiencing moderate to critical symptoms exhibited higher levels of GFAP in their CSF compared to those without. Elevated CSF levels of GFAP and S100B were also found in COVID-19 patients with decreased consciousness and comorbidities. This MR analysis provided evidence that SARS-CoV-2 may invade the human nervous system, as indicated by the increased levels of CSF biomarkers CHI3L1, NGF-β, and KLK6 in COVID-19 patients. These findings suggested that neuroinflammation could be a potential mechanism underlying the neurological complications seen in COVID-19 patients.
进行了孟德尔随机化（MR）分析，以研究严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是否侵入人类神经系统。这一点通过在新型冠状病毒肺炎（COVID-19）患者的脑脊液（CSF）和血浆中发现的生物标志物增加得到了证实。为了证实SARS-CoV-2的神经侵袭特性，利用MR可获取的数据集进行了一系列分析。此外，通过在一项回顾性队列研究中检测特定蛋白质进行了外部验证，该研究包括40例有神经系统并发症的COVID-19患者和15例疾病对照（DC）。我们的调查显示，COVID-19的住院情况、严重程度增加了某些脑区的面积和体积，但未发现脑成像衍生表型（IDP）对COVID-19有其他显著的因果效应。值得注意的是，COVID-19住院显著增加了左侧尾侧中额回的面积和体积（分别为p_fdr = 0.012；p_fdr = 0.012）。此外，COVID-19的严重程度与右侧尾侧前扣带回皮质的面积、体积以及右侧楔叶皮质的体积有关（分别为p_fdr = 0.023；p_fdr = 0.025；p_fdr = 0.026）。在COVID-19患者的CSF中，几丁质酶3样蛋白1（CHI3L1）的中位数水平（13677 pg/mL）显著高于DC组（8421 pg/mL，p < 1.00E - 04）。在CSF激肽释放酶6（KLK6）和神经生长因子β（NGF-β）中也发现了类似趋势。此外，COVID-19组血浆中神经调节蛋白（NRGN）的中位数水平（1013.00 pg/mL）显著高于对照组（360.00 pg/mL，p = 6.50E - 03）。亚组分析表明，与无症状的COVID-19患者相比，出现中度至重症症状的患者CSF中胶质纤维酸性蛋白（GFAP）水平更高。在意识下降和有合并症的COVID-19患者中也发现CSF中GFAP和S100B水平升高。这项MR分析提供了证据，表明SARS-CoV-2可能侵入人类神经系统，如COVID-19患者CSF生物标志物CHI3L1、NGF-β和KLK6水平升高所示。这些发现表明，神经炎症可能是COVID-19患者出现神经系统并发症的潜在机制。
