Chen Mengfei, Pekosz Andrew, Villano Jason S, Shen Wenjuan, Zhou Ruifeng, Kulaga Heather, Li Zhexuan, Smith Amy, Gurung Asiana, Beck Sarah E, Witwer Kenneth W, Mankowski Joseph L, Ramanathan Murugappan, Rowan Nicholas R, Lane Andrew P
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Baltimore, Maryland, USA.
J Clin Invest. 2024 Mar 14;134(8):e174439. doi: 10.1172/JCI174439.
SARS-CoV-2 infection of the upper airway and the subsequent immune response are early, critical factors in COVID-19 pathogenesis. By studying infection of human biopsies in vitro and in a hamster model in vivo, we demonstrated a transition in nasal tropism from olfactory to respiratory epithelium as the virus evolved. Analyzing each variant revealed that SARS-CoV-2 WA1 or Delta infect a proportion of olfactory neurons in addition to the primary target sustentacular cells. The Delta variant possessed broader cellular invasion capacity into the submucosa, while Omicron displayed enhanced nasal respiratory infection and longer retention in the sinonasal epithelium. The olfactory neuronal infection by WA1 and the subsequent olfactory bulb transport via axon were more pronounced in younger hosts. In addition, the observed viral clearance delay and phagocytic dysfunction in aged olfactory mucosa were accompanied by a decline of phagocytosis-related genes. Further, robust basal stem cell activation contributed to neuroepithelial regeneration and restored ACE2 expression postinfection. Together, our study characterized the nasal tropism of SARS-CoV-2 strains, immune clearance, and regeneration after infection. The shifting characteristics of viral infection at the airway portal provide insight into the variability of COVID-19 clinical features, particularly long COVID, and may suggest differing strategies for early local intervention.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）对上呼吸道的感染以及随后的免疫反应是冠状病毒病（COVID-19）发病机制中的早期关键因素。通过在体外对人体活检组织以及在体内仓鼠模型中研究感染情况，我们证明随着病毒进化，鼻嗜性从嗅觉上皮向呼吸上皮转变。分析每个变体发现，SARS-CoV-2 WA1或德尔塔变体除了主要靶标支持细胞外，还感染一部分嗅觉神经元。德尔塔变体对黏膜下层具有更广泛的细胞侵袭能力，而奥密克戎变体则表现出增强的鼻腔呼吸道感染能力以及在鼻窦上皮中的更长滞留时间。WA1对嗅觉神经元的感染以及随后通过轴突向嗅球的转运在年轻宿主中更为明显。此外，在老年嗅觉黏膜中观察到的病毒清除延迟和吞噬功能障碍伴随着吞噬相关基因的下降。此外，强大的基底干细胞激活有助于神经上皮再生并在感染后恢复血管紧张素转换酶2（ACE2）的表达。总之，我们的研究描述了SARS-CoV-2毒株的鼻嗜性、免疫清除以及感染后的再生情况。气道入口处病毒感染的变化特征为深入了解COVID-19临床特征的变异性，尤其是长期新冠症状，提供了线索，并可能提示早期局部干预的不同策略。
