Sarbecoviruses such as SARS and SARS-CoV-2 have been responsible for two major outbreaks in humans, the latter resulting in a global pandemic. While sarbecoviruses primarily cause an acute respiratory infection, they have been shown to infect the nervous system. However, mechanisms of sarbecovirus neuroinvasion and neuropathogenesis remain unclear. In this study, we examined the infectivity and trans-synaptic transmission potential of the sarbecoviruses SARS and SARS-CoV-2 in human stem cell–derived neural model systems. We demonstrated limited ability of sarbecoviruses to infect and replicate in human stem cell–derived neurons. Furthermore, we demonstrated an inability of sarbecoviruses to transmit between synaptically connected human stem cell–derived neurons. Finally, we determined an absence of SARS-CoV-2 infection in olfactory neurons in experimentally infected ferrets. Collectively, this study indicates that sarbecoviruses exhibit low potential to infect human stem cell–derived neurons, lack an ability to infect ferret olfactory neurons, and lack an inbuilt molecular mechanism to utilise retrograde axonal trafficking and trans-synaptic transmission to spread within the human nervous system.

SARS 和 SARS-CoV-2 等 Sarbeco 病毒导致人类两次重大疫情暴发，后者导致全球大流行。虽然沙贝克病毒主要引起急性呼吸道感染，但它们已被证明可以感染神经系统。然而，sarbecovirus 神经侵袭和神经发病机制仍不清楚。在这项研究中，我们检查了 sarbecoviruses SARS 和 SARS-CoV-2 在人类干细胞衍生的神经模型系统中的感染性和跨突触传播潜力。我们证明了 sarbecoviruses 在人类干细胞衍生的神经元中感染和复制的能力有限。此外，我们证明了 sarbecoviruses 无法在突触连接的人类干细胞衍生神经元之间传播。最后，我们确定实验感染雪貂的嗅觉神经元不存在 SARS-CoV-2 感染。总的来说，这项研究表明，sarbecoviruses 感染人类干细胞衍生神经元的潜力较低，缺乏感染雪貂嗅觉神经元的能力，并且缺乏利用逆行轴突运输和跨突触传递在人类神经内传播的内在分子机制系统。