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.

抽象的 过度炎症反应是流感或 SARS 感染患者疾病严重程度和死亡的主要原因。 冠状病毒-2。在严重的情况下，巨噬细胞反应失调会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仍然很大程度上未知，特别是在 COVID-19 肺部。 有趣的是，我们和其他人发现免疫感应簇细胞异位存在于肺泡区域 （实质）感染 H1N1 (PR8) 病毒后的功能尚不清楚。我们的初步数据表明，这些 簇细胞源自薄壁组织中的异位基底细胞（也称为豆荚细胞）。更重要的是，簇状细胞 减少和消融导致巨噬细胞积累减少，提高存活率和更好的恢复， 伴随着IL-25水平的下降。 Notch 信号传导的药理抑制可减少异位细胞的数量 PR8 感染的肺中的簇状细胞。这些发现得出簇细胞增强巨噬细胞积累的假设 通过 Il-25 并通过 Notch 抑制减少簇细胞衍生，从而减弱过多的巨噬细胞 反应并改善肺功能。我们制定了两个具体目标来进一步检验该假设。目标1：确定 感染流感或 SARS-CoV-2 后簇细胞是否通过 Il-25 调节巨噬细胞反应。我们将 还使用新型 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簇细胞衍生，并减弱了病毒感染的巨噬细胞反应 肺。 In this aim, we will delete Rbpjk in pod cells and use a novel Notch decoy to inhibit Notch signaling.一起这个 该项目将为簇细胞在驱动巨噬细胞失调中所发挥的作用提供第一个机制见解 病毒感染的肺部的反应。它还将提供减少簇细胞分化和减弱簇细胞分化的新方法 过度炎症。