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。我们有 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。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 病毒负荷的变化。重要的是，在 IFN-γ 中和后观察到的保护作用增强并未在 ILC2 缺陷小鼠。本提案中的研究旨在确定 ILC2 在 对流感和继发细菌感染的抵抗力。根据我们的初步数据，我们假设 IFN-γ信号减弱ILC2先天效应功能并导致组织减少 体内平衡和宿主生存。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。目标是首次确定：1) ILC2 在介导 CA04 流感感染抵抗力中的作用； 2）ILC2在调节中的作用 流感后对继发细菌感染的易感性。最终目标是获得一个 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

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.

病毒 - 细菌共同感染期间的疾病耐受性。

• 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