Pre-Existing Atopy and Respiratory Viral Infections

摘要 呼吸道合胞病毒（RSV）感染导致210万门诊就诊和58，000例住院治疗， 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人住院和死亡，死亡率与流感相似。人类数据显示， 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具有保护作用， 小鼠模型已经显示出对预先存在的特应性的流感介导的死亡的保护;然而， 这种保护机制尚不清楚。使用屋尘螨模型的特应性，我们发现， 在用小鼠1型副流感病毒（仙台病毒; SeV，一种与RSV密切相关的鼠病毒）感染之前， 防止了致命病毒剂量的死亡。这种存活依赖于CD 11 c+细胞， neureglin-1（NRG 1）。NRG 1似乎保护气道上皮免受病毒的侵害。发布了两个警报 屋尘螨模型IL 33和TSLP诱导CD 11 c+细胞产生NRG 1。CD 11 c+细胞来自 异位小鼠或外源性NRG 1在体外可降低气道上皮细胞中的病毒复制，NRG 1显著降低气道上皮细胞中的病毒复制。 降低体内死亡率。根据我们的数据，我们提出假设，预先存在的特应性保护， 呼吸道病毒在IL 33-TSLP依赖性过程中诱导的死亡率，该过程驱动CD 11 c+细胞产生 NRG 1，其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 小鼠模型以及小鼠和人气道上皮细胞培养物来检验这些假设，我们建议：（I） 确定特应性小鼠中产生NRG 1的细胞，并确定特应性介导的 从通常致命的SeV感染中存活下来。(II)确定NRG 1对上皮细胞功能的影响， 保护免受呼吸道病毒的侵害。在完成这项建议后，我们将确定和 表征了特应性小鼠肺中产生NRG 1的细胞， 在SeV感染的特应性小鼠中介导存活，以及在NRG 1的发育中对alarmin的需求 产生细胞并随后从病毒感染中存活。此外，我们将机械地 表征了NRG 1对上皮细胞的作用，并确定了NRG 1作为治疗药物的潜力。 剂这些发现构成了未来研究的基础，以探索预防死亡的治疗干预措施 从呼吸道病毒感染，具有很大的潜力，以改变严重的呼吸道病毒感染的医疗保健。

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.