Animal models recapitulating distinctive features of severe COVID-19 are critical to enhance our understanding of SARS-CoV-2 pathogenesis. Transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) under the cytokeratin 18 promoter (K18-hACE2) represent a lethal model of SARS-CoV-2 infection. The precise mechanisms of lethality in this mouse model remain unclear. Here, we evaluated the spatiotemporal dynamics of SARS-CoV-2 infection for up to 14 days post-infection. Despite infection and moderate pneumonia, rapid clinical decline or death of mice was invariably associated with viral neuroinvasion and direct neuronal injury (including brain and spinal neurons). Neuroinvasion was observed as early as 4 dpi, with virus initially restricted to the olfactory bulb supporting axonal transport via the olfactory neuroepithelium as the earliest portal of entry. No evidence of viremia was detected suggesting neuroinvasion occurs independently of entry across the blood brain barrier. SARS-CoV-2 tropism was not restricted to ACE2-expressing cells (e.g., AT1 pneumocytes), and some ACE2-positive lineages were not associated with the presence of viral antigen (e.g., bronchiolar epithelium and brain capillaries). Detectable ACE2 expression was not observed in neurons, supporting overexpression of ACE2 in the nasal passages and neuroepithelium as more likely determinants of neuroinvasion in the K18-hACE2 model. Although our work incites caution in the utility of the K18-hACE2 model to study global aspects of SARS-CoV-2 pathogenesis, it underscores this model as a unique platform for exploring the mechanisms of SARS-CoV-2 neuropathogenesis that may have clinical relevance acknowledging the growing body of evidence that suggests COVID-19 may result in long-standing neurologic consequences.

中文翻译：

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K18-hACE2 小鼠的致命神经侵袭和 SARS-CoV-2 嗜性部分独立于 hACE2 表达

概括严重 COVID-19 独特特征的动物模型对于增强我们对 SARS-CoV-2 发病机制的理解至关重要。在细胞角蛋白 18 启动子 (K18-hACE2) 下表达人血管紧张素转换酶 2 (hACE2) 的转基因小鼠代表了 SARS-CoV-2 感染的致死模型。这种小鼠模型中的确切致死机制仍不清楚。在这里，我们评估了 SARS-CoV-2 感染后长达 14 天的时空动态。尽管感染和中度肺炎，小鼠的快速临床衰退或死亡总是与病毒性神经侵袭和直接神经元损伤（包括脑和脊髓神经元）有关。早在 4 dpi 就观察到神经侵袭，病毒最初仅限于通过嗅觉神经上皮作为最早进入入口的嗅球支持轴突运输。没有检测到病毒血症的证据表明神经侵袭的发生独立于穿过血脑屏障的进入。SARS-CoV-2 嗜性不限于表达 ACE2 的细胞（例如 AT1 肺细胞），一些 ACE2 阳性谱系与病毒抗原（例如细支气管上皮和脑毛细血管）的存在无关。在神经元中未观察到可检测的 ACE2 表达，这支持了 ACE2 在鼻道和神经上皮中的过度表达，这更可能是 K18-hACE2 模型中神经侵袭的决定因素。尽管我们的工作在使用 K18-hACE2 模型研究 SARS-CoV-2 发病机制的全球方面时引起了谨慎，