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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

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.

摘要