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 K01 提案的最初前提是气道宿主防御蛋白 Short Palate Lung Nasal 上皮细胞 Clone-1（PLUNC、SPLUNC1）调节炎症，因此可能导致急性肺损伤 CF 和呼吸道感染中的损伤（ALI）和组织损伤。我们定义了一种新的免疫调节作用 SPLUNC1 增强 LPS 诱导的 IFNγ/IFNλ 相关炎症，这使我们重新关注过去几年的研究 K01 奖针对甲型流感病毒 (IAV) 肺炎模型，其中 IFN 反应至关重要。这导致 提交我们的 R01 提案“甲型流感感染期间 ALI 的 SPLUNC1 控制机制”。 IAV 死亡率主要是由于肺部炎症和急性肺损伤 (ALI) 引发的呼吸衰竭所致。因此，一个 更好地了解 IAV 引起的肺部炎症和 ALI 的驱动机制是一个关键的未满足的问题 需要。 IAV 激活内体 Toll 样受体 (TLR3/7/8/9) 以诱导气道中的干扰素 (IFN) 免疫细胞，引发炎症并导致 ALI。这一过程背后的机制并不完全 目前尚无特定疗法可以预防 ALI 或加速其缓解。 我们最近发现气道宿主防御蛋白 PLUNC 可能会增加肺部炎症和 通过增强 IFNλ 表达来治疗 ALI。 IFNλ 通过 IFN 刺激的基因增加免疫细胞的募集， 增加肺部炎症和急性肺损伤。 PLUNC 可以通过充当核酸的支架来调节 IFN 免疫信号蛋白，类似于其他具有 TLR 结合基序的宿主防御肽。 PLUNC 有双重 免疫调节特性和抗病毒作用可减少早期上皮炎症，但可能 在临床过程后期增强肺部炎症和 ALI。 在最近的工作中，我们表明 Plunc-/- 小鼠的 IFNλ 诱导受损，从而保护它们免受 LPS- 诱发肺部炎症和 ALI。我们的初步数据现在表明 Plunc-/- 小鼠受到类似的保护 在 IAV 感染期间，PLUNC 可能通过与 TLR3 的相互作用来调节这种效应。我们将测试 假设 PLUNC 通过与 TLR3 相互作用调节肺部炎症，并且阻断 PLUNC 控制的炎症可减少 IAV 感染期间的 ALI。我们将定义 PLUNC 控制的 ALI 可以调节以降低 IAV 发病率和死亡率的机制。我们将完成这个 通过这些目标： 目标 1. 明确 PLUNC 增强 IFN 反应和肺功能的机制 IAV感染期间的炎症；目标 2. 确定抑制 PLUNC 的治疗潜力，以预防 IAV-ALI并加速其恢复；目标 3. 定义 PLUNC 调节的免疫反应和单细胞 与 ALI 相关的转录组图谱及其在人类中的解决。了解 PLUNC-TLR3 的作用 ALI 中的相互作用将为限制 IAV 发病率提供治疗靶点。这里提出的机制提供了 这是一个限制 IAV 对数百万人影响的发展机会。我们将使用这个 扩展以支持该提案的初步数据生成，该提案因 COVID-19 大流行而中断。