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.

近期感染新型冠状病毒肺炎（Corona Virus Disease 2019, COVID-19）的患者，在感染早期即可出现嗅觉、味觉等感觉功能的神经异常症状。明确此类感觉功能损伤的细胞与分子机制，对于阐释该疾病临床表征的发病机制，以及确立后遗症与复发的治疗靶点均至关重要。此前缺乏基于合适人类外周神经模型的相关研究，阻碍了对COVID-19发病机制的深入理解。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的分子病理过程。本研究采用人类胚胎干细胞（human embryonic stem cell, hESC）分化获得的外周神经元构建体外模型，用以模拟多数COVID-19患者在感染早期或后续发展为后遗症时所经历的症状对应的细胞与分子病理变化。由hESC分化得到的外周神经元表达病毒入侵受体ACE2，并可通过ACE2通路直接被SARS-CoV-2感染。感染SARS-CoV-2的人类外周神经元，呈现出与嗅觉或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型。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。