Elucidating the roles of alveolar macrophage inflammation and self renewal duringinfluenza infection

阐明流感感染期间肺泡巨噬细胞炎症和自我更新的作用

• 批准号: 10652322
• 负责人: Jie Sun
• 金额: $ 45.17万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652322
• 关键词: Aging; Alveolar Macrophages; Binding; Cessation of life; Complex; Defect; Development; Disease; Elderly; Exhibits; Functional disorder; Future; Genes; Genetic; Glycolysis; HIF1A gene; Homeostasis; Immune response; Impairment; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Influenza A virus; Ligands; Lower Respiratory Tract Infection; Lung; Lung diseases; Macrophage; Mediating; Metabolic; Metabolic Pathway; Mitochondria; Molecular; Myeloid Cells; Names; Natural Immunity; Natural regeneration; Parabiosis; Pathway interactions; Population; Preventive; Production; Proliferating; Pulmonary Inflammation; Recovery; Repression; Role; Signal Transduction; TCF7L2 gene; Techniques; Therapeutic; Tissues; Upper Respiratory Infections; Virus Diseases; aged; aging population; anti-influenza; antiviral immunity; beta catenin; cancer cell; global health; in vitro activity; in vivo; influenza infection; lung injury; lung repair; monocyte; novel; pharmacologic; protein complex; response; self-renewal; stem; stem cell proliferation; tissue repair

Summary/Abstract Influenza A virus (IAV) constitutes an ongoing threat to global health. IAV infection is especially problematic in aged individuals, with estimated close to 90% IAV-associated deaths occurring in the elderly. Alveolar macrophages (AMs) are the primary lung macrophage population that are important in lung homeostasis, anti-viral immunity and tissue recovery. AMs exhibit stem-like features of self-renewal, but also can rapidly produce pro-inflammatory mediators upon stimulation, which could potentially contribute to pulmonary inflammation and injury during IAV infection. Little is known currently about the mechanisms modulating AM proliferative and inflammatory fate decisions in vivo, and the subsequent effects on tissue inflammation and recovery following IAV infection. In this application, we hypothesize that the interplay of b-catenin, HIF1-a and TCF-4 modulates AM self-renewal and inflammatory activity, thereby regulating pulmonary inflammation and tissue repair during IAV infection. Furthermore, we hypothesize that exaggerated b- catenin-HIF1-a expression dictates the aging-associated defects in AM self-renewal and function, thereby leading to severe pulmonary diseases and/or defective lung repair following IAV infection in aged hosts. Three specific Aims are proposed. Aim 1: To elucidate the associated-mechanisms by which b- catenin/HIF1-a complex modulates AM inflammatory activity and self-renewal, and subsequent effects on host diseases and recovery from IAV infection. Aim 2: To define the underlying mechanisms by which TCF- 4 regulates AM development, self-renewal and/or inflammation during homeostasis and following IAV infection. Aim 3: To determine the roles of dysregulated AM b-catenin/HIF1-a axis in contributing to aging- associated defects in AM function and regeneration, thereby causing severe IAV-associated diseases in aged hosts.

摘要/摘要 甲型流感病毒(IAV)对全球健康构成持续威胁。IAV感染尤其成问题 在老年人中，估计近90%与IAV相关的死亡发生在老年人中。牙槽骨 巨噬细胞(AM)是主要的肺巨噬细胞群，在肺内稳态中起重要作用。 抗病毒免疫和组织恢复。AM显示出自我更新的茎状特征，但也可以迅速 在刺激下产生促炎介质，这可能会对肺 IAV感染过程中的炎症和损伤。目前对AM的调节机制知之甚少 在体内决定增殖和炎症的命运，以及随后对组织炎症和 IAV感染后的康复。在这个应用中，我们假设b-连环蛋白，hif1-a的相互作用 而TCF-4调节AM的自我更新和炎症活动，从而调节肺组织 IAV感染过程中的炎症和组织修复。此外，我们假设夸张的b- 连环蛋白-HIF1-α的表达决定了AM自我更新和功能的衰老相关缺陷，从而 在老年宿主感染IAV后导致严重的肺部疾病和/或肺修复缺陷。 提出了三个具体目标。目的1：阐明b-半乳糖的相关机制。 连环蛋白/HIF1-a复合体调节AM炎症活动和自我更新，以及随后对AM的影响 宿主疾病和从IAV感染中恢复。目标2：确定技术合作框架-- 4在动态平衡和IAV后调节AM的发育、自我更新和/或炎症 感染。目的3：探讨AM b-catenin/HIF1-a轴在衰老中的作用。 AM功能和再生的相关缺陷，从而导致严重的IAV相关疾病 上了年纪的主人。

项目成果

Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination.

• DOI: 10.1126/sciimmunol.add4853
• 发表时间: 2022-10-28
• 期刊: Science immunology
• 影响因子: 24.8

T resident helper cells promote humoral responses in the lung.

• DOI: 10.1126/sciimmunol.abb6808
• 发表时间: 2021-01-08
• 期刊: Science immunology
• 影响因子: 24.8
• 作者: Swarnalekha N;Schreiner D;Litzler LC;Iftikhar S;Kirchmeier D;Künzli M;Son YM;Sun J;Moreira EA;King CG
• 通讯作者: King CG

Immune signatures underlying post-acute COVID-19 lung sequelae.

• DOI: 10.1126/sciimmunol.abk1741
• 发表时间: 2021-11-12
• 期刊: Science immunology
• 影响因子: 24.8
• 作者: Cheon IS;Li C;Son YM;Goplen NP;Wu Y;Cassmann T;Wang Z;Wei X;Tang J;Li Y;Marlow H;Hughes S;Hammel L;Cox TM;Goddery E;Ayasoufi K;Weiskopf D;Boonyaratanakornkit J;Dong H;Li H;Chakraborty R;Johnson AJ;Edell E;Taylor JJ;Kaplan MH;Sette A;Bartholmai BJ;Kern R;Vassallo R;Sun J
• 通讯作者: Sun J

Persistent B Cell-Derived MHC Class II Signaling Is Required for the Optimal Maintenance of Tissue-Resident Helper T Cells.

组织驻留辅助 T 细胞的最佳维持需要持续的 B 细胞衍生的 MHC II 类信号传导。

• DOI: 10.4049/immunohorizons.2300093
• 发表时间: 2024
• 期刊: ImmunoHorizons
• 作者: Son,YoungMin;Cheon,InSu;Li,Chaofan;Sun,Jie
• 通讯作者: Sun,Jie

Aging and respiratory viral infection: from acute morbidity to chronic sequelae.

• DOI: 10.1186/s13578-021-00624-2
• 发表时间: 2021-06-22
• 期刊: Cell & bioscience
• 影响因子: 7.5
• 作者: Wu Y;Goplen NP;Sun J
• 通讯作者: Sun J