Tuft Cells Modulate Macrophage Response Following Lung Viral Infection

簇细胞调节肺部病毒感染后的巨噬细胞反应

• 批准号: 10453066
• 负责人: Jianwen Que
• 金额: $ 24.3万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453066
• 关键词: 2019-nCoV; Ablation; Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Alveolar; Attenuated; Automobile Driving; Basal Cell; COVID-19; COVID-19 pandemic effects; Cell Differentiation process; Cells; Cessation of life; Coronavirus Infections; Data; Derivation procedure; Genetic; Immune; Infection; Infiltration; Inflammation; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Intestines; Knock-in Mouse; Lead; Ligands; Lung; Mediator of activation protein; Modeling; Molecular; Monitor; Mus; Patients; Persons; Pharmacologic Substance; Pharmacology; Play; Reagent; Recovery; Role; SARS-CoV-2 infection; Sentinel; Severity of illness; Signal Transduction; Source; Structure of parenchyma of lung; Survival Rate; Tamoxifen; Testing; Therapeutic; Trachea; Virus; Virus Diseases; cytokine; improved; influenza infection; insight; lung preservation; lung regeneration; macrophage; mortality; mouse model; neutralizing antibody; notch protein; novel; novel strategies; pulmonary function; response; side effect; single cell analysis; therapeutic target

ABSTRACT The hyperinflammatory response is a major cause of disease severity and death in patients infected by influenza or SARS- CoV-2. In severe cases dysregulated macrophage responses contribute to the progression of acute respiratory distress syndrome (ARDS). Nevertheless, how macrophages are activated remains largely unknown, especially in COVID-19 lungs. Intriguingly, we and others found that the immune sensing tuft cells are ectopically present in the alveolar region (parenchyma) following infection by H1N1 (PR8) virus with unclarified functions. Our preliminary data show that these tuft cells are derived from ectopic basal cells (also known as pod cells) in the parenchyma. More importantly, tuft cell reduction and ablation result in reduced macrophage accumulation, improved survival rate and better recovery, accompanied by the decreased level of Il-25. Pharmacological inhibition of Notch signaling reduces the numbers of ectopic tuft cells in PR8-infected lungs. These findings lead to the hypothesis that tuft cells enhance macrophage accumulation through Il-25 and that reducing tuft cell derivation through Notch inhibition attenuates excessive macrophage responses and improves lung function. We formulate two specific aims to further test the hypothesis. Aim1: To determine whether tuft cells modulate macrophage responses through Il-25 upon infection with influenza or SARS-CoV-2. We will also use a novel R26hACE2 mouse line to build the first targeted SARS-CoV-2 infection model. Aim 2: To test the hypothesis that Notch inhibition reduces tuft cell derivation from pod cells and attenuates macrophage responses in virus-infected lungs. In this aim, we will delete Rbpjk in pod cells and use a novel Notch decoy to inhibit Notch signaling. Together this project will provide the first mechanistic insights into the role played by tuft cells in driving dysregulated macrophage responses in virus-infected lungs. It will also offer new approaches to reduce tuft cell differentiation and attenuate hyperinflammation.

摘要 在感染流感或SARS的患者中，高炎症反应是疾病严重程度和死亡的主要原因- CoV-2。在严重病例中，巨噬细胞反应失调导致急性呼吸窘迫的进展 综合征(ARDS)。然而，巨噬细胞是如何被激活的在很大程度上仍不清楚，特别是在新冠肺炎的肺中。 有趣的是，我们和其他人发现免疫感应簇状细胞异位存在于肺泡区。 (实质)被功能不明的H1N1(PR8)病毒感染后。我们的初步数据显示，这些 丛生细胞来源于薄壁组织中异位的基细胞(也称为豆荚细胞)。更重要的是，簇状细胞 减少和消融巨噬细胞堆积，提高存活率和更好的恢复， 伴随着IL-25水平的下降。药物抑制Notch信号可减少异位数目 PR8感染肺中的簇状细胞。这些发现导致了一种假设，即簇状细胞促进巨噬细胞聚集 通过IL-25和通过抑制Notch减少绒毛细胞来源来减弱过度的巨噬细胞 回应并改善肺功能。我们制定了两个具体的目标来进一步检验这一假设。目标1：确定 在感染流感或SARS-CoV-2时，簇状细胞是否通过IL-25调节巨噬细胞的反应。我们会 还利用一种新的R26hACE2小鼠系构建了第一个靶向SARS-CoV-2感染模型。目标2：检验假设 Notch抑制减少了豆荚细胞的丛生细胞，并减弱了病毒感染的巨噬细胞反应 肺部。为此，我们将删除豆荚细胞中的Rbpjk，并使用一种新的Notch诱饵来抑制Notch信号。把这个放在一起 该项目将首次对丛生细胞在驱动调节失调的巨噬细胞中所起的作用提供机械性的见解 病毒感染的肺部的反应。它还将提供新的方法来减少丛生细胞的分化和衰减 过度炎症。