Benavides Feline F W, Veldhuis Kroeze Edwin J B, Leijten Lonneke, Schmitz Katharina S, van Run Peter, Kuiken Thijs, de Vries Rory D, Bauer Lisa, van Riel Debby
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
PLoS One. 2025 Apr 7;20(4):e0311449. doi: 10.1371/journal.pone.0311449. eCollection 2025.
Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) can cause systemic disease, including neurological complications, even after mild respiratory disease. Previous studies have shown that SARS-CoV-2 infection can induce neurovirulence through microglial activation in the brains of patients and experimentally inoculated animals, which are models representative for moderate to severe respiratory disease. Here, we aimed to investigate the neuroinvasive and neurovirulent potential of SARS-CoV-2 in intranasally inoculated ferrets, a model for subclinical to mild respiratory disease. The presence of viral RNA, histological lesions, virus-infected cells, and the number and surface area of microglia and astrocytes were investigated. Viral RNA was detected in various respiratory tissue samples by qPCR at 7 days post inoculation (dpi). Virus antigen was detected in the nasal turbinates of ferrets sacrificed at 7 dpi and was associated with inflammation. Viral RNA was detected in the brains of ferrets sacrificed 7 dpi, but in situ hybridization nor immunohistochemistry did confirm evidence for viral RNA or antigen in the brain. Histopathological analysis of the brains showed no evidence for an influx of inflammatory cells. Despite this, we observed an increased number of Alzheimer type II astrocytes in the hindbrains of SARS-CoV-2 inoculated ferrets. Additionally, we detected increased microglial activation in the olfactory bulb and hippocampus, and a decrease in the astrocytic activation status in the white matter and hippocampus of SARS-CoV-2 inoculated ferrets. In conclusion, although SARS-CoV-2 has limited neuroinvasive potential in this model for subclinical to mild respiratory disease, there is evidence for neurovirulent potential. This study highlights the value of this ferret model to study the neuropathogenecity of SARS-CoV-2 and reveals that a mild SARS-CoV-2 infection can affect both microglia and astrocytes in different parts of the brain.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）即使在轻度呼吸道疾病后也可引起全身性疾病，包括神经并发症。先前的研究表明，SARS-CoV-2感染可通过患者大脑和实验接种动物（代表中度至重度呼吸道疾病的模型）中的小胶质细胞激活诱导神经毒性。在此，我们旨在研究SARS-CoV-2在经鼻接种雪貂（一种亚临床至轻度呼吸道疾病模型）中的神经侵袭和神经毒性潜力。研究了病毒RNA的存在、组织学病变、病毒感染细胞以及小胶质细胞和星形胶质细胞的数量和表面积。接种后7天（dpi）通过qPCR在各种呼吸道组织样本中检测到病毒RNA。在7 dpi处死的雪貂的鼻甲中检测到病毒抗原，并且与炎症相关。在7 dpi处死的雪貂的大脑中检测到病毒RNA，但原位杂交和免疫组织化学均未证实在大脑中有病毒RNA或抗原的证据。对大脑的组织病理学分析未显示炎症细胞流入的证据。尽管如此，我们观察到接种SARS-CoV-2的雪貂的后脑中有更多数量的阿尔茨海默II型星形胶质细胞。此外，我们在接种SARS-CoV-2的雪貂的嗅球和海马中检测到小胶质细胞激活增加，而在白质和海马中的星形胶质细胞激活状态降低。总之，尽管SARS-CoV-2在这种亚临床至轻度呼吸道疾病模型中的神经侵袭潜力有限，但有证据表明其具有神经毒性潜力。这项研究突出了这种雪貂模型在研究SARS-CoV-2神经致病性方面的价值，并揭示轻度SARS-CoV-2感染可影响大脑不同部位的小胶质细胞和星形胶质细胞。
