SARS-CoV-2 infects and damages the mature and immature olfactory sensory neurons of hamsters

Zhang, Anna Jinxia; Lee, Andrew Chak-Yiu; Chu, Hin; Chan, Jasper Fuk-Woo; Fan, Zhimeng; Li, Can; Liu, Feifei; Chen, Yanxia; Yuan, Shuofeng; Poon, Vincent Kwok-Man; Chan, Chris Chung-Sing; Cai, Jian-Piao; Wu, Kenneth Lap-Kei; Sridhar, Siddharth; Chan, Ying-Shing; Yuen, Kwok-Yung

BACKGROUND: Coronavirus Disease 2019 (COVID-19) is primarily an acute respiratory tract infection. Distinctively, a substantial proportion of COVID-19 patients develop olfactory dysfunction of uncertain underlying mechanism which can be severe and prolonged. The roles of inflammatory obstruction of the olfactory clefts leading to conductive impairment, inflammatory cytokines affecting olfactory neuronal function, destruction of olfactory neurons or their supporting cells, and direct invasion of olfactory bulbs, in causing olfactory dysfunction are uncertain. METHODS: In this study, we investigated the location for the pathogenesis of SARS-CoV-2 from the olfactory epithelium (OE) of the nasopharynx to the olfactory bulb of golden Syrian hamsters. RESULTS: After intranasal inoculation with SARS-CoV-2, inflammatory cell infiltration and proinflammatory cytokine/chemokine responses were detected in the nasal turbinate tissues which peaked between 2 to 4 days post-infection with the highest viral load detected at day 2 post-infection. Besides the nasopharyngeal pseudo-columnar ciliated respiratory epithelial cells, SARS-CoV-2 viral antigens were also detected in the more superficial mature olfactory sensory neurons labeled by olfactory marker protein (OMP), the less mature olfactory neurons labelled by Tuj1 at more basal position, and the sustentacular cells which provide metabolic and physical support for the olfactory neurons, resulting in apoptosis and severe destruction of the OE. During the whole course of infection, SARS-CoV-2 viral antigens were not detected in the olfactory bulb. CONCLUSIONS: Besides acute inflammation at OE, infection of mature and immature olfactory neurons, and the supporting sustentacular cells by SARS-CoV-2 may contribute to the unique olfactory dysfunction of COVID-19 which is not reported with SARS-CoV.