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

基本信息

批准号：
10555330
负责人：
Jianwen Que
金额：
$ 20.25万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10555330
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 Macrophage Mediator Modeling Molecular Monitor Mus Patients Persons Pharmacologic Substance Play Pod cells Reagent Recovery Role SARS-CoV-2 infection Sensory 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 mortality mouse model neutralizing antibody notch protein novel novel strategies pharmacologic pulmonary function response side effect single cell analysis therapeutic target

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 Macrophage Mediator Modeling Molecular Monitor Mus Patients Persons Pharmacologic Substance Play Pod cells Reagent Recovery Role SARS-CoV-2 infection Sensory 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 mortality mouse model neutralizing antibody notch protein novel novel strategies pharmacologic pulmonary function response side effect single cell analysis therapeutic target

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项目摘要

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.

抽象的高炎症反应是流感或SARS-感染的患者疾病严重程度和死亡的主要原因 COV-2。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，如何激活巨噬细胞在很大程度上仍然未知，尤其是在19009肺中。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）H1N1（PR8）病毒感染具有未闪烁的功能。我们的初步数据表明这些簇细胞来自实质中的异位基底细胞（也称为POD细胞）。更重要的是，簇状细胞减少和消融会导致巨噬细胞的积累降低，提高存活率和更好的恢复，伴随着IL-25的降低。 Notch信号的药理抑制作用减少了异位的数量 PR8感染肺中的簇细胞。这些发现导致了簇状细胞增强巨噬细胞积累的假设通过IL-25并通过缺口抑制减少簇状细胞衍生的巨噬细胞减轻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，以进一步检验该假设。 AIM1：确定簇细胞是否在感染流感或SARS-COV-2后通过IL-25调节巨噬细胞反应。我们将还使用新型的R26HACE 2小鼠系列来构建第一个靶向的SARS-COV-2感染模型。目标2：检验假设 Notch抑制作用可减少POD细胞中的簇状细胞衍生物，并减轻感染病毒感染的巨噬细胞反应肺。在此目标中，我们将删除POD细胞中的RBPJK，并使用新型的诱饵来抑制Notch信号传导。在一起项目将对簇细胞在驱动失调的巨噬细胞中所扮演的作用提供第一个机械见解病毒感染的肺部反应。它还将提供新的方法来减少簇细胞分化和减弱高炎症。