Center of Evolutionary and Theoretical Immunology, Biology Department, University of New Mexico, NM, USA.
Department of Biology, Texas State University, San Marcos, TX, USA.
Brain Behav Immun. 2022 May;102:341-359. doi: 10.1016/j.bbi.2022.03.006. Epub 2022 Mar 17.
Anosmia, loss of smell, is a prevalent symptom of SARS-CoV-2 infection. Anosmia may be explained by several mechanisms driven by infection of non-neuronal cells and damage in the nasal epithelium rather than direct infection of olfactory sensory neurons (OSNs). Previously, we showed that viral proteins are sufficient to cause neuroimmune responses in the teleost olfactory organ (OO). We hypothesize that SARS-CoV-2 spike (S) protein is sufficient to cause olfactory damage and olfactory dysfunction. Using an adult zebrafish model, we report that intranasally delivered SARS-CoV-2 S RBD mostly binds to the non-sensory epithelium of the olfactory organ and causes severe olfactory histopathology characterized by loss of cilia, hemorrhages and edema. Electrophysiological recordings reveal impaired olfactory function to both food and bile odorants in animals treated intranasally with SARS-CoV-2 S RBD. However, no loss of behavioral preference for food was detected in SARS-CoV-2 S RBD treated fish. Single cell RNA-Seq of the adult zebrafish olfactory organ indicated widespread loss of olfactory receptor expression and inflammatory responses in sustentacular, endothelial, and myeloid cell clusters along with reduced numbers of T. Combined, our results demonstrate that intranasal SARS-CoV-2 S RBD is sufficient to cause structural and functional damage to the zebrafish olfactory system. These findings may have implications for intranasally delivered vaccines against SARS-CoV-2.
嗅觉丧失（anosmia）是 SARS-CoV-2 感染的一种常见症状。嗅觉丧失可能是由感染非神经元细胞和鼻上皮损伤引起的多种机制导致的，而不是嗅觉感觉神经元（OSN）的直接感染。此前，我们表明，病毒蛋白足以引起硬骨鱼嗅觉器官（OO）中的神经免疫反应。我们假设 SARS-CoV-2 刺突（S）蛋白足以引起嗅觉损伤和嗅觉功能障碍。使用成年斑马鱼模型，我们报告称，鼻内递送的 SARS-CoV-2 S RBD 主要与嗅觉器官的非感觉上皮结合，并导致严重的嗅觉组织病理学特征，包括纤毛丧失、出血和水肿。电生理记录显示，用 SARS-CoV-2 S RBD 鼻内处理的动物对食物和胆汁气味的嗅觉功能受损。然而，在 SARS-CoV-2 S RBD 处理的鱼中未检测到对食物的行为偏好丧失。成年斑马鱼嗅觉器官的单细胞 RNA-Seq 表明，在支持细胞、内皮细胞和髓样细胞簇中广泛丧失嗅觉受体表达和炎症反应，同时 T 细胞数量减少。综上所述，我们的结果表明，鼻内 SARS-CoV-2 S RBD 足以对斑马鱼嗅觉系统造成结构和功能损伤。这些发现可能对 SARS-CoV-2 的鼻内递送疫苗具有重要意义。
