Innate Immunity and Viral Infection in Asthma

在这次AADCRC计划的更新中，我们将重点关注三个关键的和未被研究的先天免疫因素 以及它们如何影响哮喘的病毒感染：表面活性物质的阴离子磷脂(棕榈酰基- 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)。因为这些介体有互补的功能来调节 炎症和免疫在哮喘和感染中的作用，我们提出了三个相互关联、协同、独立的观点 研究这些介体如何协调与病毒相关的新的先天性免疫反应的项目 哮喘的感染。我们将研究三种在呼吸道疾病中具有不同影响的病毒，以及 确定先天反应是如何防御它们的。具体来说，我们将重点关注鼻病毒C(RV-C)，一种 已知的哮喘恶化因子，可导致严重疾病；甲型流感，一种对哮喘仍有影响的病毒 模棱两可和SARS-CoV-2，一种可导致严重肺部疾病但哮喘可能不是 风险因素，并可能实际上提供保护。我们展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具有保护作用，因为它是产生IL-13所必需的 可溶性ST2，进而在甲型流感感染期间减弱IL-33的作用；以及3)SP-A和2型 细胞因子通过抑制SARS-CoV-2感染在哮喘效应和起始阶段发挥保护作用 SARS-CoV-2受体ACE2通过影响转录受体的表达和功能 结合和下游的促炎信号。因此，所有这些先天免疫成分似乎 预防哮喘中的病毒感染。我们令人兴奋的初步数据支持了我们计划的总体 假设POPG/PI、Tollip和SP-A作为独特的免疫调节剂发挥作用，从而减弱 特定病毒感染(RV-C、甲型流感和SARS-CoV-2)对2型哮喘的影响。因此， 补充功能性POPG/PI、SP-A和IL-33诱骗受体Sst2可能是新的策略 预防因病毒感染而加重的哮喘。项目1将严格测试POPG/PI和SP的活性- 作为一种新的分子工具的补充剂，用于干扰由RV-C引起的感染，RV-C是一种已知可加剧 哮喘。项目2将确定Tollip如何预防哮喘患者由甲型流感引起的病毒恶化 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如何协同保护 通过抑制ACE2介导的感染和IL-6信号通路抗SARS-CoV-2感染。我们 还包括行政核心和临床核心，这两个核心平等地为所有项目提供服务。我们建立在 20多年来在相互作用的内在分子机制方面的富有成效的合作 哮喘的II型炎症和病毒加重。我们三个项目之间的强大协同作用将 通过证明先天免疫成分在 研究预防哮喘的病毒感染。

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.