Innate Immunity and Viral Infection in Asthma

在这个AADCRC项目更新中，我们将重点关注三个关键的和未充分研究的先天免疫因子 以及它们如何影响哮喘中的病毒感染：表面活性剂的阴离子磷脂（棕榈酰- 油酰-磷脂酰甘油，POPG，和磷脂酰肌醇，PI），Toll相互作用蛋白（Tollip），和 表面活性蛋白-A（SP-A）。因为这些介质具有互补的调节功能， 炎症和免疫在哮喘和感染中，我们提出三个相互关联，协同作用， 研究这些介质如何协调与病毒相关的新型先天免疫反应的项目 哮喘的感染。我们将研究三种病毒对呼吸道疾病的影响， 决定了先天反应是如何抵御它们的具体来说，我们将重点关注鼻病毒C（RV-C）， 一种已知的可导致严重疾病的哮喘恶化因子; A型流感病毒，其对哮喘的影响仍然存在 SARS-CoV-2是一种可导致严重肺部疾病的病毒，但哮喘可能不是一种 风险因素，实际上可以提供保护。我们显示了创新的初步数据表明，1）POPG，PI 和SP-A减弱RV-C感染; 2）Tollip表现出保护作用，因为IL-13需要产生 可溶性ST 2，其又减弱A型流感感染期间IL-33的作用;和3）SP-A和2型 细胞因子通过抑制SARS-CoV-2在哮喘中感染的效应期和起始期提供保护， ACE 2的表达和功能，SARS-CoV-2受体，通过对转录的影响，受体 结合和下游促炎信号传导。因此，所有这些先天免疫成分似乎 防止哮喘病毒感染。我们令人兴奋的初步数据支持我们的计划的整体 假设POPG/PI、Tollip和SP-A作为独特免疫调节剂起作用， 特异性病毒感染（RV-C、甲型流感和SARS-CoV-2）对2型哮喘的影响。因此，我们认为， 补充功能性POPG/PI、SP-A和IL-33诱饵受体sST 2可能是新的策略 对抗病毒感染引起的哮喘恶化。项目1将严格测试POPG/PI和SP的活动- 一种补充剂，作为一种新的分子工具，用于破坏RV-C引起的感染，RV-C是一种已知会加剧 哮喘项目2将确定Tollip如何保护哮喘患者免受甲型流感引起的病毒性加重 通过抑制IL-33信号传导。项目3将确定2型细胞因子和SP-A如何协同作用， 通过抑制ACE 2介导的感染和IL-6信号通路来对抗SARS-CoV-2感染。我们 还包括一个行政核心和一个临床核心，两者都平等地为所有项目服务。我们建立在 20多年来，在内在分子机制方面的富有成效的合作， 2型炎症和病毒性哮喘恶化。我们三个项目之间的强大协同作用将 通过证明先天性免疫成分在免疫系统中的作用， 一项研究表明，哮喘患者可以预防病毒感染。

In this AADCRC program renewal, we will focus on three critical and understudied innate immune factors and how they impact viral infections in asthma: the anionic phospholipids of surfactant (palmitoyl- oleoyl-phosphatidylglycerol, POPG, and phosphatidylinositol, PI), Toll interacting protein (Tollip), and surfactant protein-A (SP-A). Because these mediators have complementary functions to modulate inflammation and immunity in asthma and infection, we propose three interrelated, synergistic, self-standing projects to investigate how these mediators orchestrate novel innate immune responses associated with viral infections in asthma. We will study three viruses with a spectrum of effects in airway disease, and determine how innate responses protect against them. Specifically, we will focus on rhinovirus C (RV-C), a known exacerbator of asthma that can cause severe disease; influenza A, a virus whose effect in asthma remains ambiguous and SARS-CoV-2, a virus that can cause severe lung disease, but for which asthma may not be a risk factor, and may in fact confer protection. We show innovative preliminary data indicating that 1) POPG, PI and SP-A attenuate RV-C infection; 2) Tollip exhibits protective effects as it is required for IL-13 to generate soluble ST2 that in turn attenuates the effects of IL-33 during influenza A infection; and 3) SP-A and type 2 cytokines confer protection in the effector and initiation phases of SARS-CoV-2 infection in asthma by inhibiting the expression and function of ACE2, the SARS-CoV-2 receptor, through effects upon transcription, receptor binding and downstream pro-inflammatory signaling. Thus, all these innate immune components appear to protect against viral infections in asthma. Our exciting preliminary data underpin our program’s overall hypothesis that POPG/PI, Tollip and SP-A function as unique immune modulators that attenuate the impact of specific viral infections (RV-C, Influenza A and SARS-CoV-2) in type-2 asthma. Therefore, supplementation of functional POPG/PI, SP-A and the IL-33 decoy receptor sST2 may be novel strategies against asthma exacerbations due to viral infections. Project 1 will critically test the activity of POPG/PI and SP- A supplementation as a novel molecular tool for disrupting infections due to RV-C, a virus known to exacerbate asthma. Project 2 will determine how Tollip protects against viral exacerbations caused by influenza A in asthma through inhibition of IL-33 signaling. Project 3 will determine how type-2 cytokines and SP-A synergize to protect against SARS-CoV-2 infection through inhibition of ACE2-mediated infection and IL-6 signaling pathways. We also include an Administrative Core and a Clinical Core, both which serve all projects equally. We build upon productive collaborations of over 20 years on innate molecular mechanisms underlying the interaction between type 2 inflammation and viral exacerbations of asthma. The strong synergy among our three projects will accelerate progress toward novel therapies by demonstrating that the innate immune components under study protect against viral infection in asthma.