SPLUNC1 and Neutrophilic Inflammation in Cystic Fibrosis

SPLUNC1 与囊性纤维化中的中性粒细胞炎症

• 批准号: 10393271
• 负责人: Clemente Britto-Leon
• 金额: $ 6.99万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2022-01-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393271
• 关键词: Acute Lung Injury; Antiviral Agents; Automobile Driving; Binding; Bioinformatics; COVID-19 pandemic; Cells; Chemistry; Clinical; Cystic Fibrosis; Data; Development; Epithelial; Generations; Genes; Host Defense; Human; Immune; Immune response; Immune signaling; Immunology; Impairment; Individual; Infection; Inflammation; Influenza; Influenza A virus; Infrastructure; Innate Immune Response; Interferon Type II; Interferons; Lung; Lung Inflammation; Mentored Research Scientist Development Award; Morbidity - disease rate; Mus; Nasal Epithelium; Nucleic Acids; Palate; Peptides; Process; Property; Proteins; Recovery; Resolution; Respiratory Failure; Respiratory Tract Infections; Role; Signal Transduction; Signaling Protein; Structure of parenchyma of lung; TLR3 gene; Testing; Therapeutic; Toll-like receptors; Virus Diseases; Work; cystic fibrosis infection; immunoregulation; mortality; neutrophil; novel; pathogen; pneumonia model; prevent; receptor; recruit; response; scaffold; therapeutic target; transcriptome

The original premise of our K01 proposal was that airway host-defense protein Short Palate Lung Nasal epithelium Clone-1 (PLUNC, SPLUNC1) regulates inflammation and therefore could contribute to acute lung injury (ALI) and tissue damage in CF and respiratory infections. We defined a novel immunomodulatory effect of SPLUNC1 in enhancing LPS-induced IFNγ/IFNλ-associated inflammation that led us to refocus the last years of the K01 award on an Influenza A virus (IAV) model of pneumonia, where IFN responses are critical. This led to the submission of our R01 proposal "SPLUNC1-controlled mechanisms of ALI during influenza A infection". IAV mortality is largely due to respiratory failure, precipitated by lung inflammation and ALI. Therefore, a better understanding of the mechanisms that drive lung inflammation and ALI caused by IAV is a critical unmet need. IAV activates endosomal Toll-Like Receptors (TLR3/7/8/9) to induce Interferons (IFN) in airway and immune cells, driving inflammation and causing ALI. The mechanisms underlying this process are not fully understood and there are no specific therapies to prevent ALI or accelerate its resolution. We recently discovered that airway host defense protein PLUNC may increase lung inflammation and ALI by enhancing IFNλ expression. IFNλ increases immune cell recruitment through IFN-stimulated genes, that increase lung inflammation and ALI. PLUNC may modulate IFN by serving as a scaffold for nucleic acids and immune signaling proteins, similar to other host defense peptides with TLR-binding motifs. PLUNC has dual immunomodulatory properties and antiviral effects that decrease early epithelial inflammation but may enhance lung inflammation and ALI later in the clinical course. In recent work we showed that Plunc-/- mice have impaired IFNλ induction that protects them from LPS- induced lung inflammation and ALI. Our preliminary data now show that Plunc-/- mice are similarly protected during IAV infection and that PLUNC may modulate this effect through interactions with TLR3. We will test the hypothesis that PLUNC regulates lung inflammation through interactions with TLR3, and that blocking PLUNC-controlled inflammation decreases ALI during IAV infection. We will define PLUNC-controlled ALI mechanisms that can be modulated to decrease the morbidity and mortality of IAV. We will accomplish this through these aims: Aim 1. Define the mechanisms by which PLUNC increases IFN responses and lung inflammation during IAV infection; Aim 2. Define the therapeutic potential of inhibiting PLUNC to protect against IAV-ALI and accelerate its recovery; and Aim 3. Define PLUNC-regulated immune response and single-cell transcriptome profiles associated with ALI and its resolution in humans. Understanding the role of PLUNC-TLR3 interactions in ALI will provide therapeutic targets to limit IAV morbidity. The mechanisms proposed here offer an opportunity for developments that would limit the impact of IAV on millions of individuals. We will use this extension to support preliminary data generation for this proposal, disrupted by the COVID-19 pandemic.

我们的K01提案的原始前提是气道宿主防御蛋白短pa肺鼻音 上皮克隆-1（plunc，splunc1）调节注射，因此可能有助于急性肺 CF和呼吸道感染的损伤（ALI）和组织损伤。我们定义了一种新颖的免疫调节作用 SPLUNC1在增强LPS诱导的IFNγ/IFNλ相关注射中，这使我们重新集中了最后几年 IFN反应至关重要的肺炎的流感病毒（IAV）模型的K01奖。这导致了 我们的R01提案的提交“影响力在Atractza A感染期间Ali的Splunc1控制机制”。 IAV死亡率很大程度上是由于呼吸衰竭，肺部注射和ALI沉淀。因此， 更好地理解驱动肺注射和由IAV引起的ALI的机制是关键 需要。 IAV激活内体电话样受体（TLR3/7/8/9），以诱导气道中的干扰素（IFN），并且 免疫细胞，驱动炎症并引起ALI。该过程的基础机制尚未完全 理解，并且没有具体的疗法来防止ALI或加速其解决方案。 我们最近发现，气道宿主防御蛋白斑块可能会增加肺注射和 通过增强IFNλ表达来通过ALI。 IFNλ通过IFN刺激的基因增加免疫细胞的募集， 增加肺注射和ALI。 PLUNC可能会通过作为核酸的支架来调节IFN和 免疫信号蛋白，类似于具有TLR结合基序的其他宿主防御肽。 plunc具有双重 免疫调节特性和抗病毒作用会降低早期上皮影响，但可能 在临床过程中增强肺部炎症和ALI。 在最近的工作中，我们表明plunc - / - 小鼠损害了IFNλ诱导，可保护它们免受LPS-的侵害。 诱导肺注射和ALI。我们的初步数据现在表明plunc - / - 小鼠受到类似保护 在IAV感染期间，该血液可能通过与TLR3的相互作用来调节这种影响。我们将测试 假设通过与TLR3的相互作用来调节肺注射，并阻止 IAV感染期间，Plunc控制的注射会下降ALI。我们将定义板状控制的阿里 可以调节以降低IAV的发病率和死亡率的机制。我们将实现这一目标 通过这些目的：目标1。定义PLUNC增加IFN反应和肺的机制 IAV感染期间的炎症；目标2。定义抑制板的治疗潜力 IAV-ALI并加速其恢复； AIM 3。定义毛线调节的免疫响应和单细胞 与Ali相关的转录组轮廓及其在人类中的分辨率。了解plunc-tlr3的作用 ALI中的相互作用将提供治疗靶标，以限制IAV发病率。这里提出的机制提供 一个发展的机会，将限制IAV对数百万个人的影响。我们将使用这个 扩展以支持该提案的初步数据生成，并被Covid-19的大流行破坏。