Wang Xuefei, Dong Meng, Wu Xinchao, Schnepf Daniel, Thiel Julia, Sun Wenfei, Wolfrum Christian, Li Sisi, Jin Wenfei, Staeheli Peter, Ye Liang
Department of Immunology, International Cancer Center, Shenzhen University Medical School, Shenzhen, China.
Shenzhen Key Laboratory of Gene Regulation, Department of Systems Biology School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
J Virol. 2025 Mar 18;99(3):e0141324. doi: 10.1128/jvi.01413-24. Epub 2025 Feb 4.
Type III interferons (IFNs) primarily act on epithelial cells and protect against virus infection of the mucosa, whereas type I IFNs act more systemically. To date, it has been unknown which epithelial subtypes in the upper airways, the primary site for initial infection for most respiratory viruses, primarily rely on type III IFN or type I IFNs for antiviral protection. To address this question, we performed a single-cell transcriptomics analysis of the epithelial IFN-mediated response focusing on the upper airways of mice. This work identified nine distinct cell types derived from the olfactory epithelium and thirteen distinct cell types from the respiratory epithelium. Interestingly, type I IFNs induced a stronger antiviral transcriptional response than type III IFN in respiratory epithelial cells, whereas in olfactory epithelial cells, including sustentacular (SUS) and Bowman's gland cells (BGC), type III IFN was more dominant compared to type I IFN. SUS and BGC, which provide structural support and maintain the integrity of olfactory sensory neurons, were highly susceptible to infection with a mouse-adapted variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 MA20) but were protected against infection if the animals were prophylactically treated with type III IFN. These findings demonstrate a high degree of cell type heterogeneity in terms of interferon-mediated antiviral responses and reveal a potent role for type III IFNs in protecting the olfactory epithelium.IMPORTANCESARS-CoV-2 infects SUS and BGC in the olfactory epithelium, causing an impairment of structural support and integrity of olfactory sensory neurons that can result in severe olfactory dysfunctions. We observed an unexpected compartmentalization of the IFN-mediated transcriptional response within the airway epithelium, and we found that olfactory epithelial cells preferentially respond to type III IFN, which resulted in robust antiviral protection of SUS and BGC. Given the proximity of the olfactory epithelium to the central nervous system, we hypothesize that evolution favored a type III IFN-biased antiviral immune response in this tissue to limit inflammatory responses in the brain. Cell type-specific antiviral responses in the upper airways, triggered by the different types of IFNs, should be investigated in more detail and carefully taken into consideration during the development of IFN-based antivirals for clinical use.
III型干扰素（IFN）主要作用于上皮细胞，保护黏膜免受病毒感染，而I型干扰素的作用更具全身性。迄今为止，尚不清楚上呼吸道（大多数呼吸道病毒的初始感染主要部位）中的哪些上皮亚型主要依靠III型干扰素或I型干扰素进行抗病毒保护。为了解决这个问题，我们对小鼠上呼吸道上皮细胞中干扰素介导的反应进行了单细胞转录组学分析。这项研究确定了源自嗅觉上皮的9种不同细胞类型和源自呼吸道上皮的13种不同细胞类型。有趣的是，I型干扰素在呼吸道上皮细胞中诱导的抗病毒转录反应比III型干扰素更强，而在嗅觉上皮细胞中，包括支持细胞（SUS）和鲍曼腺细胞（BGC），III型干扰素比I型干扰素更占主导地位。SUS和BGC为嗅觉感觉神经元提供结构支持并维持其完整性，它们对严重急性呼吸综合征冠状病毒2（SARS-CoV-2 MA20）的小鼠适应变体高度敏感，但如果动物接受III型干扰素预防性治疗，则可免受感染。这些发现表明，在干扰素介导的抗病毒反应方面存在高度的细胞类型异质性，并揭示了III型干扰素在保护嗅觉上皮方面的重要作用。
重要性
SARS-CoV-2感染嗅觉上皮中的SUS和BGC，导致嗅觉感觉神经元的结构支持和完整性受损，进而可能导致严重的嗅觉功能障碍。我们观察到气道上皮内干扰素介导的转录反应存在意想不到的分区现象，并且发现嗅觉上皮细胞优先对III型干扰素作出反应，从而对SUS和BGC产生强大的抗病毒保护作用。鉴于嗅觉上皮与中枢神经系统相邻，我们推测进化有利于该组织中偏向III型干扰素的抗病毒免疫反应，以限制大脑中的炎症反应。在开发用于临床的基于干扰素的抗病毒药物时，应更详细地研究上呼吸道中由不同类型干扰素触发的细胞类型特异性抗病毒反应，并予以认真考虑。
