Direct neuronal infection of SARS-CoV-2 reveals cellular and molecular pathology of chemosensory impairment of COVID-19 patients

Patients with recent pandemic coronavirus disease 19 (COVID-19) complain of neurological abnormalities in sensory functions such as smell and taste in the early stages of infection. Determining the cellular and molecular mechanism of sensory impairment is critical to understand the pathogenesis of clinical manifestations, as well as in setting therapeutic targets for sequelae and recurrence. The absence of studies utilizing proper models of human peripheral nerve hampers an understanding of COVID-19 pathogenesis. Here, we report that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly infects human peripheral sensory neurons, leading to molecular pathogenesis for chemosensory impairments. An in vitro system utilizing human embryonic stem cell (hESC)-derived peripheral neurons was used to model the cellular and molecular pathologies responsible for symptoms that most COVID-19 patients experience early in infection or may develop as sequelae. Peripheral neurons differentiated from hESCs expressed viral entry factor ACE2, and were directly infected with SARS-CoV-2 via ACE2. Human peripheral neurons infected with SARS-CoV-2 exhibited impaired molecular features of chemosensory function associated with abnormalities in sensory neurons of the olfactory or gustatory organs. Our results provide new insights into the pathogenesis of chemosensory dysfunction in patients with COVID-19.

近期罹患新型冠状病毒肺炎（Coronavirus Disease 2019, COVID-19）的患者，在感染早期常出现以嗅觉、味觉等感觉功能异常为表现的神经系统症状。阐明感觉功能损伤的细胞与分子机制，对于理解该类临床表现的发病机制，以及为后遗症与复发患者制定治疗靶点均至关重要。此前缺乏基于合适的人类外周神经模型的相关研究，阻碍了对COVID-19发病机制的解析。本研究证实，严重急性呼吸综合征冠状病毒2（Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2）可直接感染人类外周感觉神经元，进而引发化学感觉功能损伤相关的分子病理过程。本研究采用人类胚胎干细胞（human embryonic stem cell, hESC）诱导分化的外周神经元构建体外模型，以模拟多数COVID-19患者在感染早期出现或后续可发展为后遗症的相关症状所对应的细胞与分子病理特征。由hESC诱导分化得到的外周神经元可表达病毒入侵受体ACE2，并可通过ACE2途径被SARS-CoV-2直接感染。感染SARS-CoV-2的人类外周感觉神经元，可出现与嗅觉、味觉器官感觉神经元异常相关的化学感觉功能分子特征受损表现。本研究结果为COVID-19患者化学感觉功能障碍的发病机制提供了全新的研究视角。