State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China.
Department of Respiratory Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 10010, China.
EBioMedicine. 2023 Mar;89:104457. doi: 10.1016/j.ebiom.2023.104457. Epub 2023 Feb 3.
Zika virus (ZIKV) is an emerging arbovirus of the genus flavivirus that is associated with congenital Zika syndrome (CZS) in newborns. A wide range of clinical symptoms including intellectual disability, speech delay, coordination or movement problems, and hearing and vision loss, have been well documented in children with CZS. However, whether ZIKV can invade the olfactory system and lead to post-viral olfactory dysfunction (PVOD) remains unknown.
We investigated the susceptibility and biological responses of the olfactory system to ZIKV infection using mouse models and human olfactory organoids derived from patient olfactory mucosa.
We demonstrate that neonatal mice infected with ZIKV suffer from transient olfactory dysfunction when they reach to puberty. Moreover, ZIKV mainly targets olfactory ensheathing cells (OECs) and exhibits broad cellular tropism colocalizing with small populations of mature/immature olfactory sensory neurons (mOSNs/iOSNs), sustentacular cells and horizontal basal cells in the olfactory mucosa (OM) of immunodeficient AG6 mice. ZIKV infection induces strong antiviral immune responses in both the olfactory mucosa and olfactory bulb tissues, resulting in the upregulation of proinflammatory cytokines/chemokines and genes related to the antiviral response. Histopathology and transcriptomic analysis showed typical tissue damage in the olfactory system. Finally, by using an air-liquid culture system, we showed that ZIKV mainly targets sustentacular cells and OECs and support robust ZIKV replication.
Our results demonstrate that olfactory system represents as significant target for ZIKV infection, and that PVOD may be neglected in CZS patients.
Stated in the acknowledgment.
寨卡病毒（ZIKV）是黄病毒属中的一种新兴虫媒病毒，与新生儿先天性寨卡综合征（CZS）有关。患有 CZS 的儿童中广泛记录了多种临床症状，包括智力残疾、言语延迟、协调或运动问题以及听力和视力丧失。然而，寨卡病毒是否可以侵入嗅觉系统并导致病毒性嗅觉功能障碍（PVOD）尚不清楚。
我们使用小鼠模型和源自患者嗅粘膜的人嗅类器官研究了嗅觉系统对 ZIKV 感染的易感性和生物学反应。
我们证明感染寨卡病毒的新生小鼠在青春期时会短暂出现嗅觉功能障碍。此外，寨卡病毒主要靶向嗅鞘细胞（OEC），并在免疫缺陷型 AG6 小鼠嗅粘膜（OM）中表现出广泛的细胞嗜性，与成熟/未成熟嗅觉感觉神经元（mOSNs/iOSNs）、支持细胞和水平基底细胞的小群体共定位。寨卡病毒感染在嗅粘膜和嗅球组织中诱导强烈的抗病毒免疫反应，导致促炎细胞因子/趋化因子和与抗病毒反应相关的基因上调。组织病理学和转录组分析显示嗅觉系统存在典型的组织损伤。最后，通过使用气液培养系统，我们表明寨卡病毒主要靶向支持细胞和 OEC，并支持寨卡病毒的大量复制。
我们的研究结果表明，嗅觉系统是寨卡病毒感染的重要靶标，而在 CZS 患者中可能会忽视 PVOD。
见致谢中说明。
