Innate immune responses to SARS-CoV-2 infection in the olfactory epithelium

嗅觉上皮细胞对 SARS-CoV-2 感染的先天免疫反应

基本信息

批准号：
10445837
负责人：
Qizhi Gong
金额：
$ 58.64万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445837
关键词：
2019-nCoV ACE2 Acute Animal Model Anosmia Apical Axon Biological Assay Brain COVID-19 Cell Culture System Cell Culture Techniques Cells Chronic Clinical Engineering Environment Exhibits Fluorescence-Activated Cell Sorting Functional disorder Goals Human Immune Infection Inflammation Inflammatory Response Innate Immune Response K-18 conjugate Lead Mediating Microbe Molecular Mouse Strains Mus Neurologic Symptoms Neurons Nose Olfactory Epithelium Olfactory Mucosa Olfactory dysfunction Pathogenicity Pathway interactions Patients Process Regulation Reporter Reporting Research SARS-CoV-2 infection SARS-CoV-2 positive Signal Transduction Symptoms TLR4 gene Testing Thick Tissues Transcript Transgenic Organisms Viral Virus Diseases Virus Replication cell type chemokine coronavirus disease cribriform plate cytokine genetic manipulation innate immune function insight mouse model nervous system disorder neuroepithelium novel olfactory bulb olfactory receptor olfactory sensory neurons pathogenic virus post SARS-CoV-2 infection receptor receptor downregulation receptor expression response seal single-cell RNA sequencing sustentacular cell transcription factor

项目摘要

RESEARCH SUMMARY Sudden-onset of olfactory loss has been recognized as a common COVID-19 symptom. The mechanism of COVID-19 related olfactory dysfunction is unknown. Whether the degree of olfactory deficit is indicative of any long-term neurological diseases in COVID-19 has not been evaluated. Recent single-cell RNA-seq analyses revealed that the receptor for SARS-CoV-2, ACE2, is not expressed by olfactory sensory neurons (OSNs) but are expressed by supporting sustentacular (Sus) cells in the OE. Therefore, Sus cells may be the entry cell type for SARS-CoV-2 in the OE. SARS-CoV-2 infection in the OE needs to be further characterized. Current observations indicate that the viral infection is sparse and localized. Widespread olfactory receptor downregulation has been reported under viral infection suggesting that there might be a distributed viral impact from localized viral infection in the OE. We hypothesize that widespread Sus cell mediated inflammatory response, triggered by SARS-CoV-2, is responsible for COVID-19 associated olfactory loss. In this study, we will characterize inflammatory responses to SARS-CoV-2 in the olfactory epithelium and identify Sus cell specific cytokine expressions; we will established a primary Sus cell culture system to examine viral recognition pathways and transcription factors involved in SARS-CoV-2 induced innate immune responses; we will further determine SARS-CoV-2 infection induced olfactory sensory neuron functional deficits. Through this study, we will gain mechanistic insight into COVID-19 associated olfactory loss.

研究概要突然发生的嗅觉丧失已被认为是一种常见的 COVID-19 症状。其机制为 COVID-19 相关的嗅觉功能障碍尚不清楚。嗅觉缺陷的程度是否预示着任何尚未对 COVID-19 引起的长期神经系统疾病进行评估。最近的单细胞 RNA-seq 分析研究表明，SARS-CoV-2 的受体 ACE2 不由嗅觉感觉神经元 (OSN) 表达，而是由嗅觉感觉神经元 (OSN) 表达由 OE 中的支持细胞 (Sus) 表达。因此，Sus细胞可能是入口细胞 OE 中的 SARS-CoV-2 类型。 OE 中的 SARS-CoV-2 感染需要进一步确定特征。当前的观察表明，病毒感染是稀疏且局部的。广泛的嗅觉受体据报道，病毒感染下的下调表明可能存在分布式病毒影响来自 OE 中的局部病毒感染。我们假设广泛的 Sus 细胞介导炎症由 SARS-CoV-2 触发的反应是导致 COVID-19 相关嗅觉丧失的原因。在这项研究中，我们将表征嗅觉上皮细胞中对 SARS-CoV-2 的炎症反应并识别 Sus 细胞特定的细胞因子表达；我们将建立原代Sus细胞培养系统来检测病毒 SARS-CoV-2 诱导的先天免疫反应中涉及的识别途径和转录因子；我们将进一步确定SARS-CoV-2感染引起的嗅觉感觉神经元功能缺陷。通过这个通过这项研究，我们将深入了解与 COVID-19 相关的嗅觉丧失的机制。