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 炎症反应过度是流感或SARS患者疾病严重程度和死亡的主要原因- 二型冠状病毒在严重的情况下，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，巨噬细胞如何被激活在很大程度上仍然未知，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地存在于肺泡区域 （薄壁组织）感染后的H1N1（PR 8）病毒与不明功能。我们的初步数据显示， 簇细胞来源于薄壁组织中的异位基底细胞（也称为荚细胞）。更重要的是， 减少和消融导致减少的巨噬细胞积聚，提高的存活率和更好的恢复， 伴随着IL-25水平的降低。Notch信号传导的药理学抑制减少了异位免疫的数量。 PR 8感染的肺中的簇状细胞。这些发现导致了这样的假设，即簇状细胞增强巨噬细胞的积累 通过IL-25，通过Notch抑制减少簇状细胞衍生， 反应和改善肺功能。我们制定了两个具体的目标，以进一步测试的假设。目的1：确定 在感染流感病毒或SARS-CoV-2后，簇状细胞是否通过IL-25调节巨噬细胞应答。我们将 还利用新型R26 hACE 2小鼠系建立了第一个靶向SARS-CoV-2感染模型。目的2：检验假设 Notch抑制减少了来自豆荚细胞的簇状细胞，并减弱了病毒感染的巨噬细胞的反应， 肺在这个目标中，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。一起这么 该项目将提供第一个机制的见解所发挥的作用，簇细胞在驱动失调的巨噬细胞 病毒感染肺部的反应。它还将提供新的方法，以减少簇细胞分化和衰减 过度炎症