Pre-Existing Atopy and Respiratory Viral Infections

已有的特应性和呼吸道病毒感染

基本信息

批准号：
10658075
负责人：
Mitchell H Grayson
金额：
$ 72.28万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-24 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658075
关键词：
2019-nCoV 5 year old Adoptive Transfer Age Years Air Allergic Disease Antibodies Asthma CD14 gene Caring Cell Culture Techniques Cell physiology Cells Cellular Infiltrate Cessation of life Child Cytoprotection Data Dendritic Cells Development Disease Dose Elderly Epithelial Cells Future Genetic Transcription Goals Green Fluorescent Proteins Hematopoietic Homeostasis Hospitalization Hospitalized Child Human IL4 gene ITGAX gene Impairment In Vitro Infant Infection Inflammatory Influenza Interferons Interleukin-13 Liquid substance Lung Macrophage Activation Mediating Medical Metabolic Metaplasia Mitochondria Modeling Monoclonal Antibodies Mucous body substance Mus Neuregulin 1 Outpatients Para-Influenza Virus Type 1 Pathway interactions Process Production Publications Pyroglyphidae Respiratory Syncytial Virus Infections Respiratory syncytial virus Risk Role SARS-CoV-2 infection Sendai virus Severities Sorting Stress TSLP gene Testing Therapeutic Therapeutic Agents Therapeutic Intervention Therapeutic Studies Tight Junctions Translating Viral Viral Respiratory Tract Infection Virus Virus Diseases Virus Replication Visit airway epithelium airway hyperresponsiveness atopy eosinophil experimental study gene product human data in vivo infancy monocyte mortality mouse model novel strategies parainfluenza virus pathogenic virus peripheral blood prevent protective effect receptor respiratory response

项目摘要

Abstract Respiratory syncytial virus (RSV) infection leads to 2.1 million outpatient visits and 58,000 hospitalizations for children under 5 years of age. In those 65 years of age or older, RSV accounts for an average of 177,000 hospitalizations and 14,000 deaths annually, with similar mortality rates to influenza. Human data suggest pre- existing atopy may have a protective effect on mortality and severity of influenza and SARS-CoV-2 infection, and mouse models have shown protection from influenza mediated mortality with pre-existing atopy; however, the mechanism of this protection remains unclear. Using the house dust mite model of atopy, we found being atopic before infection with mouse parainfluenza virus type-1 (Sendai virus; SeV, a murine virus closely related to RSV), prevented mortality to an otherwise lethal viral dose. This survival depended upon CD11c+ cells, which produced neureglin-1 (NRG1). NRG1 appears to protect airway epithelium from the viral insult. Two alarmins released in the house dust mite model, IL33 and TSLP, induced NRG1 production from CD11c+ cells. CD11c+ cells from atopic mice or exogenous NRG1 reduced viral replication in airway epithelial cells in vitro and NRG1 significantly reduced mortality in vivo. Based on our data, we propose the hypothesis that pre-existing atopy protects against respiratory viral induced mortality in an IL33-TSLP dependent process that drives CD11c+ cells to produce NRG1, which restores epithelial cell homeostasis and protects epithelial cells from viral infection. Using our mouse model and mouse and human airway epithelial cell cultures to test these hypotheses, we propose to: (I) Define the NRG1 producing cell(s) in atopic mice and determine the requirement for NRG1 in atopy mediated survival from normally lethal SeV infection. (II) Determine the effect of NRG1 on epithelial cell function and protection from a respiratory viral insult. Upon completion of this proposal, we will have identified and characterized the NRG1 producing cells in the atopic mouse lung, the requirement for these cells and NRG1 in mediating survival in SeV infected atopic mice, and the requirement for alarmins in the development of the NRG1 producing cells and subsequent survival from the viral infection. In addition, we will have mechanistically characterized the effect of NRG1 on epithelial cells and determined the potential for NRG1 as a therapeutic agent. These findings form the basis for future studies to explore therapeutic interventions to prevent mortality from respiratory viral infections, with great potential to change medical care for severe respiratory viral infections.

抽象的呼吸综合病毒（RSV）感染可导致210万个门诊就诊和58,000次住院治疗 5岁以下的儿童。在那65岁或以上的65岁以上，RSV平均占177,000 每年住院和14,000人死亡，与流感相似的死亡率相似。人类数据表明 - 现有的特对流感和SARS-COV-2感染的死亡率和严重程度可能具有保护作用，以及小鼠模型表明，具有预先存在的特应二的保护症免受流感介导的死亡率的保护。但是，这种保护的机制尚不清楚。使用屋子尘螨的特应二螨模型，我们发现是特有的在感染小鼠Parainfluenza病毒1型（仙台病毒； Sev，一种与RSV密切相关的鼠病毒）之前，防止死亡率为致命的病毒剂量。这种生存取决于CD11C+细胞，该细胞产生 Neureglin-1（NRG1）。 NRG1似乎可以保护气道上皮免受病毒损伤。发出了两个警报房屋粉尘螨模型IL33和TSLP诱导CD11C+细胞的NRG1产生。 CD11C+细胞来自特应小鼠或外源性NRG1在体外和NRG1中降低了气道上皮细胞的病毒复制体内死亡率降低。基于我们的数据，我们提出了以下假设，即预先存在的特应性可以防止在IL33-TSLP依赖性过程中呼吸道病毒诱导的死亡率，该过程驱动CD11C+细胞产生 NRG1恢复上皮细胞稳态并保护上皮细胞免受病毒感染的影响。使用我们的小鼠模型和小鼠和人类气道上皮细胞培养物以检验这些假设，我们建议：（i）定义特应小鼠中的NRG1产生细胞，并确定NRG1在Atopy介导的中的需求正常致命的SEV感染中的生存。（ii）确定NRG1对上皮细胞功能的影响和防止呼吸病毒侮辱。完成此提案后，我们将确定并表征了特应小鼠肺中NRG1产生细胞的表征，这些细胞和NRG1的要求介导SEV感染的特应性小鼠的生存，以及在NRG1发展中对警报的需求产生细胞和随后的病毒感染生存期。此外，我们将有机械表征了NRG1对上皮细胞的影响，并确定了NRG1作为治疗的潜力代理人。这些发现构成了未来研究以探索治疗干预措施以防止死亡率的基础从呼吸道病毒感染中，有很大的潜力改变严重呼吸道病毒感染的医疗护理。