ILC2-Mediated Protection from Acute Lung Infection

ILC2 介导的急性肺部感染保护

• 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
• 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

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.

项目摘要 关于新描述的2型先天淋巴样细胞（ILC2）种群的信息有限 肺，这些细胞的调节及其对急性呼吸道感染的保护的影响。我们有 现在发现，IFN-γ负调节ILC2免疫表述功能，并且动物缺乏IFN-γ表达 证明对原发性H1N1大流行病毒感染以及继发性的抗药性增加 肺炎球菌感染。通过改进，可以在病毒感染的IFN-γ-/ - 小鼠中增强ILC2活性 肺组织炎症和肺IL-5，两次末期和嗜酸性粒细胞的表达增加，但无 变化病毒负担。重要的是，未观察到IFN-γ谈判后看到的增加的保护 ILC2缺乏小鼠。该提案中的研究旨在确定ILC2在 对影响力和继发细菌感染的抗性。根据我们的初步数据，我们假设 IFN-γ信号传导会降低ILC2先天效应子功能，并导致组织降低 稳态和宿主生存。为了测试这个概念，我们将探索几种独特的资源，包括 在ILC2，嗜酸性粒细胞表达和TGF-βIIR信号的缺乏的小鼠菌株中，以及我们 在研究宿主病原体相互作用方面的丰富经验。目的是首次确定：1） ILC2在介导对CA04影响力感染的抗性中的作用； 2）ILC2在调节中的作用 影响力后继发细菌感染的敏感性。最终目标是获得 了解负责保护急性呼吸道感染的过程并利用 获得的信息是为了影响预防和治疗影响力和治疗的临床方法 相关的继发细菌感染。

项目成果

Effects of Influenza on Alveolar Macrophage Viability Are Dependent on Mouse Genetic Strain.

• DOI: 10.4049/jimmunol.1701406
• 发表时间: 2018-07-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Califano D;Furuya Y;Metzger DW
• 通讯作者: Metzger DW

Evaluation of Pneumococcal Surface Protein A as a Vaccine Antigen against Secondary Streptococcus pneumoniae Challenge during Influenza A Infection.

肺炎球菌表面蛋白 A 作为疫苗抗原对抗甲型流感感染期间继发性肺炎链球菌攻击的评估。

• DOI: 10.3390/vaccines7040146
• 发表时间: 2019
• 期刊: Vaccines
• 影响因子: 7.8
• 作者: Roberts,Sean;Williams,ClareM;Salmon,SharonL;Bonin,JesseL;Metzger,DennisW;Furuya,Yoichi
• 通讯作者: Furuya,Yoichi

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

• DOI: 10.1371/journal.ppat.1009405
• 发表时间: 2021-03
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Barman TK;Racine R;Bonin JL;Califano D;Salmon SL;Metzger DW
• 通讯作者: Metzger DW

Disease Tolerance during Viral-Bacterial Co-Infections.

• DOI: 10.3390/v13122362
• 发表时间: 2021-11-25
• 期刊: Viruses
• 作者: Barman TK;Metzger DW
• 通讯作者: Metzger DW

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

• DOI: 10.1073/pnas.2118535119
• 发表时间: 2022-02-22
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Barman TK;Huber VC;Bonin JL;Califano D;Salmon SL;McKenzie ANJ;Metzger DW
• 通讯作者: Metzger DW