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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.

研究综述突然发作的嗅觉丧失被认为是一种常见的COVID-19症状。的机理 COVID-19相关的嗅觉功能障碍尚不清楚。嗅觉缺陷的程度是否表明任何尚未对COVID-19的长期神经系统疾病进行评估。最近的单细胞RNA-seq分析发现SARS-CoV-2的受体ACE 2不在嗅觉感觉神经元（OSN）中表达，支持细胞（Sustentacular，Sus）是支持细胞的主要表达细胞，因此，Sus细胞可能是支持细胞的进入细胞在OE中的SARS-CoV-2感染需要进一步表征。电流观察表明病毒感染是稀疏的和局部的。广布嗅觉感受器据报道，在病毒感染下下调，表明可能存在分布式病毒影响我们假设广泛分布的Sus细胞介导的炎性细胞因子可能是由炎症细胞介导的。由SARS-CoV-2引发的反应是COVID-19相关嗅觉丧失的原因。本研究将描述嗅上皮对SARS-CoV-2的炎症反应，本研究将建立原代Sus细胞培养体系，检测病毒的表达，识别途径和转录因子参与SARS-CoV-2诱导的先天免疫反应;我们将进一步确定SARS-CoV-2感染诱导的嗅觉感觉神经元功能缺陷。通过这个通过这项研究，我们将从机理上深入了解COVID-19相关的嗅觉丧失。