Pre-Existing Atopy and Respiratory Viral Infections

摘要 呼吸道合胞病毒(RSV)感染导致210万人次门诊和5.8万人次住院 5岁以下儿童。在65岁或以上的人群中，呼吸道合胞病毒平均占177,000 每年住院人数和14,000人死亡，死亡率与流感相似。人类数据表明， 现有的特应性疾病可能对流感和SARS-CoV-2感染的死亡率和严重程度具有保护作用，以及 小鼠模型已经显示出对流感介导的死亡的保护作用，这种保护作用是通过预先存在的特应性反应来实现的；然而， 这种保护的机制尚不清楚。使用特应性屋尘螨模型，我们发现有特应性 在感染小鼠副流感病毒1型(仙台病毒；SEV，一种与RSV关系密切的小鼠病毒)之前， 避免了致命性病毒剂量的死亡。这种存活依赖于CD11c+细胞，CD11c+细胞产生 Neureglin-1(NRG1)。NRG1似乎可以保护呼吸道上皮细胞免受病毒的攻击。两个警报器发布在 屋尘螨模型IL33和TSLP可诱导CD11c+细胞产生NRG1。CD11c+细胞来源 特应性小鼠或外源性NRG1显著抑制呼吸道上皮细胞病毒复制 降低体内死亡率。基于我们的数据，我们提出了一种假设，即先前存在的特应性疾病可以预防 呼吸道病毒诱导的死亡率在IL33-TSLP依赖的过程中驱动CD11c+细胞产生 NRG1，它可以恢复上皮细胞的动态平衡，保护上皮细胞免受病毒感染。使用我们的 为了验证这些假说，我们建议：(I) 确定特应性小鼠的NRG1产生细胞(S)并确定其在特应性反应中的需求 从通常致命的SeV感染中存活下来。(Ii)确定NRG1对上皮细胞功能的影响和 保护免受呼吸道病毒的侮辱。在完成这项建议后，我们将确定和 特应性小鼠肺中产生NRG1的细胞的特征，对这些细胞和NRG1的需求 在SEV感染的特应性小鼠中调节生存，以及在NRG1的发展中对警素的需求 产生细胞并随后从病毒感染中存活下来。此外，我们将在机械上 表征NRG1对上皮细胞的影响，并确定NRG1作为治疗药物的潜力 探员。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 来自呼吸道病毒感染，具有极大的潜力改变严重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.