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：
10570195
负责人：
Qizhi Gong
金额：
$ 59.01万
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/10570195
关键词：
2019-nCoV ACE2 Acute Animal Model Anosmia Apical Applied Genetics Axon Biological Assay Brain COVID-19 Cell Culture System Cell Culture Techniques Cell Line Cell Shape Cells Chronic Clinical Engineering Environment Exhibits Fluorescence-Activated Cell Sorting Glass Goals Human Immune Infection Inflammation Inflammatory Response Innate Immune Response K-18 conjugate Mediating Microbe Molecular Mouse Strains Mus Neurologic Symptoms Neuronal Dysfunction Neurons Nose Olfactory Epithelium Olfactory Mucosa Olfactory dysfunction Pathogenicity Pathway interactions Patients Process Receptor Down-Regulation Regulation Reporter Genes 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 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 permissiveness post SARS-CoV-2 infection receptor receptor downregulation receptor expression response seal single-cell RNA sequencing sustentacular cell transcription factor

2019-nCoV ACE2 Acute Animal Model Anosmia Apical Applied Genetics Axon Biological Assay Brain COVID-19 Cell Culture System Cell Culture Techniques Cell Line Cell Shape Cells Chronic Clinical Engineering Environment Exhibits Fluorescence-Activated Cell Sorting Glass Goals Human Immune Infection Inflammation Inflammatory Response Innate Immune Response K-18 conjugate Mediating Microbe Molecular Mouse Strains Mus Neurologic Symptoms Neuronal Dysfunction Neurons Nose Olfactory Epithelium Olfactory Mucosa Olfactory dysfunction Pathogenicity Pathway interactions Patients Process Receptor Down-Regulation Regulation Reporter Genes 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 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 permissiveness post SARS-CoV-2 infection receptor receptor downregulation receptor expression response seal single-cell RNA sequencing sustentacular cell transcription factor

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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.

研究摘要突然发作的嗅觉损失已被认为是常见的Covid-19症状。机制 COVID-19相关的嗅觉功能障碍尚不清楚。嗅觉赤字的程度是否指示 Covid-19中的长期神经疾病尚未评估。最近的单细胞RNA-seq分析揭示了SARS-COV-2 ACE2的受体并未通过嗅觉感觉神经元（OSN）表达通过支持OE中的静脉（SUS）细胞来表达。因此，SUS单元可能是入口单元在OE中输入SARS-COV-2。 OE中的SARS-COV-2感染需要进一步表征。当前的观察结果表明病毒感染稀疏且局部。广泛的嗅觉受体在病毒感染下已报告下调，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细胞介导的炎症由SARS-COV-2触发的响应是导致COVID-19相关嗅觉损失的原因。在这项研究中，我们将表征嗅觉上皮中对SARS-COV-2的炎症反应并鉴定SUS细胞特定的细胞因子表达；我们将建立一个主要的SUS细胞培养系统来检查病毒 SARS-COV-2中涉及的识别途径和转录因子诱导的先天免疫反应；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。通过这个研究，我们将获得有关COVID-19相关嗅觉损失的机械洞察力。