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.

抽象的呼吸道合胞病毒 (RSV) 感染导致 210 万人次门诊就诊和 58,000 人次住院治疗 5 岁以下儿童。在 65 岁或以上的人群中，RSV 平均占 177,000 每年有 14,000 人住院并死亡，死亡率与流感相似。人类数据表明预现有的特应性可能对流感和 SARS-CoV-2 感染的死亡率和严重程度有保护作用，并且小鼠模型已显示出对已有特应性的流感介导的死亡的保护作用；然而，这种保护机制尚不清楚。使用特应性的屋尘螨模型，我们发现特应性在感染1型小鼠副流感病毒（仙台病毒；SeV，一种与RSV密切相关的鼠科病毒）之前，防止了致命病毒剂量的死亡。这种生存依赖于 CD11c+ 细胞，它产生神经调节蛋白-1 (NRG1)。 NRG1 似乎可以保护气道上皮免受病毒侵害。释放的两种警报素屋尘螨模型 IL33 和 TSLP 诱导 CD11c+ 细胞产生 NRG1。 CD11c+ 细胞来自特应性小鼠或外源性NRG1可显着减少体外气道上皮细胞中的病毒复制，并且NRG1显着减少降低体内死亡率。根据我们的数据，我们提出这样的假设：预先存在的特应性可以预防呼吸道病毒在 IL33-TSLP 依赖性过程中诱导死亡率，该过程驱动 CD11c+ 细胞产生 NRG1，可恢复上皮细胞稳态并保护上皮细胞免受病毒感染。使用我们的小鼠模型以及小鼠和人类气道上皮细胞培养物来检验这些假设，我们建议：（I）定义特应性小鼠中 NRG1 产生细胞并确定特应性介导中对 NRG1 的需求从通常致命的 SeV 感染中存活下来。 (二)确定NRG1对上皮细胞功能的影响免受呼吸道病毒侵害的保护。完成本提案后，我们将确定并表征了特应性小鼠肺中产生 NRG1 的细胞，这些细胞和 NRG1 的需求介导 SeV 感染特应性小鼠的生存，以及 NRG1 发育过程中对警报素的需求产生细胞并随后从病毒感染中存活下来。此外，我们还将机械地表征了 NRG1 对上皮细胞的影响，并确定了 NRG1 作为治疗药物的潜力代理人。这些发现为未来探索预防死亡的治疗干预措施的研究奠定了基础呼吸道病毒感染，具有改变严重呼吸道病毒感染医疗护理的巨大潜力。