ILC2-Mediated Protection from Acute Lung Infection

ILC2 介导的急性肺部感染保护

基本信息

批准号：
10063550
负责人：
DENNIS W METZGER
金额：
$ 46.94万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-12 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063550
关键词：
Acute Acute respiratory infection Adoptive Transfer Alveolar Macrophages Amphiregulin Animals Attention Bacteria Bacterial Infections Bacterial Pneumonia Bronchoalveolar Lavage Fluid Cell physiology Cells Cessation of life Clinical Coupled Data Development Epidermal Growth Factor Epithelial Epithelial Cell Proliferation Goals Homeostasis Hospitalization Human IFNGR1 gene Immune response In Vitro Infection Inflammation Influenza Influenza A Virus, H1N1 Subtype Influenza A virus Interferon Type II Interleukin-13 Interleukin-5 Interleukin-9 Lung Lung infections Lymphoid Cell Mediating Modeling Monitor Morbidity - disease rate Mouse Strains Mus Natural regeneration Pathology Phagocytes Phase Play Pneumococcal Infections Population Predisposition Prevention approach Process Production Recovery Regulation Regulatory T-Lymphocyte Reporting Resistance Resources Respiratory System Respiratory Tract Infections Role Secondary to Signal Transduction Structure of parenchyma of lung Survival Rate T-Lymphocyte Testing Time Tissues Transforming Growth Factor beta Viral Viral Load result Virus Diseases Virus Replication base co-infection cytokine design eosinophil experience helminth infection immune function in vivo influenza infection insight lung injury microorganism interaction mortality novel pandemic disease pandemic influenza pathogen recruit special interest group therapeutically effective tissue repair

项目摘要

Project Summary There is only limited information about the newly described type 2 innate lymphoid cell (ILC2) population in the lung, the regulation of these cells, and their impact on protection against acute respiratory infections. We have now found that IFN-γ negatively regulates ILC2 immune function and that animals deficient in IFN-γ expression demonstrate increased resistance to both primary H1N1 pandemic virus infection as well as secondary pneumococcal infection. Enhanced ILC2 activity in viral-infected IFN-γ-/- mice is accompanied by decreased lung tissue inflammation and increased expression of pulmonary IL-5, amphiregulin, and eosinophils, but no change in viral burden. Importantly, the increased protection seen after IFN-γ neutralization is not observed in ILC2-deficient mice. Studies in this proposal are designed to now determine the unique role of ILC2s in resistance to influenza and secondary bacterial infections. Based on our preliminary data, we hypothesize that IFN-γ signaling diminishes ILC2 innate effector function and leads to decreased tissue homeostasis and host survival. To test this concept, we will exploit several unique resources, including novel strains of mice that are deficient in ILC2s, eosinophil expression, and TGF-βIIR signaling, as well as our extensive experience in studying host-pathogen interactions. The aims are to determine for the first time: 1) the role of ILC2s in mediating resistance to CA04 influenza infection; and 2) the role of ILC2s in regulating susceptibility to secondary bacterial infections following influenza. The ultimate goal is to obtain an understanding of the processes responsible for protection against acute respiratory infection and to exploit the information obtained in order to influence clinical approaches for prevention and treatment of influenza and associated secondary bacterial infections.

项目概要关于新描述的 2 型先天淋巴细胞 (ILC2) 群体的信息有限肺，这些细胞的调节及其对预防急性呼吸道感染的影响。现在发现 IFN-γ 负向调节 ILC2 免疫功能，并且 IFN-γ 表达缺陷的动物表现出对原发性 H1N1 大流行病毒感染以及继发性 H1N1 大流行病毒感染的抵抗力增强肺炎球菌感染时，病毒感染的 IFN-γ-/- 小鼠中 ILC2 活性增强，同时伴随着 ILC2 活性降低。肺组织炎症和肺 IL-5、双调蛋白和嗜酸性粒细胞表达增加，但没有重要的是，在 IFN-γ 中和后未观察到病毒负荷的增加。本提案中的研究旨在确定 ILC2 缺陷小鼠的独特作用。根据我们的初步数据，我们勇敢地抵抗流感和继发性细菌感染。 IFN-γ信号减弱ILC2先天效应功能并导致组织减少为了测试这个概念，我们将利用几种独特的资源，包括缺乏 ILC2、嗜酸性粒细胞表达和 TGF-βIIR 信号传导的新型小鼠品系，以及我们的在研究宿主-病原体相互作用方面拥有丰富的经验，目的是首次确定：1) ILC2 在介导 CA04 流感感染抵抗中的作用；2) ILC2 在调节中的作用；最终目标是获得流感后继发细菌感染的易感性。了解负责预防急性呼吸道感染的过程并利用为影响流感预防和治疗的临床方法而获得的信息相关的继发性细菌感染。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sequential targeting of interferon pathways for increased host resistance to bacterial superinfection during influenza.

连续靶向干扰素途径以增强流感期间宿主对细菌重复感染的抵抗力。

DOI：
发表时间：
2021
期刊：
影响因子：
6.7
作者：
Barman, Tarani Kanta;Racine, Rachael;Bonin, Jesse L;Califano, Danielle;Salmon, Sharon L;Metzger, Dennis W
通讯作者：
Metzger, Dennis W

Allergic Airway Disease Prevents Lethal Synergy of Influenza A Virus-Streptococcus pneumoniae Coinfection.

过敏性气道疾病可防止甲型流感病毒-肺炎链球菌双重感染的致命协同作用。

DOI：
发表时间：
2019
期刊：
影响因子：
6.4
作者：
Roberts, Sean;Salmon, Sharon L;Steiner, Donald J;Williams, Clare M;Metzger, Dennis W;Furuya, Yoichi
通讯作者：
Furuya, Yoichi

Bacterial Second Messenger Cyclic di-AMP Modulates the Competence State in Streptococcus pneumoniae.

细菌第二信使环二 AMP 调节肺炎链球菌的活性状态。

DOI：
发表时间：
2020
期刊：
影响因子：
3.2
作者：
Zarrella, Tiffany M;Yang, Jun;Metzger, Dennis W;Bai, Guangchun
通讯作者：
Bai, Guangchun

Design and evaluation of single-dose polyanhydride nanovaccines against bacterial respiratory pathogens

针对细菌性呼吸道病原体的单剂量聚酐纳米疫苗的设计与评价

DOI：
发表时间：
2024-09-14
期刊：
影响因子：
0
作者：
Danielle A. Wagner
通讯作者：
Danielle A. Wagner

Viral PB1-F2 and host IFN-γ guide ILC2 and T cell activity during influenza virus infection.

病毒PB1-F2 和宿主IFN-γ 在流感病毒感染期间指导ILC2 和T 细胞活性。

DOI：
发表时间：
2022-02-22
期刊：
影响因子：
11.1
作者：
Barman, Tarani Kanta;Huber, Victor C;Bonin, Jesse L;Califano, Danielle;Salmon, Sharon L;McKenzie, Andrew N J;Metzger, Dennis W
通讯作者：
Metzger, Dennis W