Regulation of Inflammatory Pathology in Invasive Aspergillosis

侵袭性曲霉病炎症病理学的调节

• 批准号: 10286538
• 负责人: Steven P Templeton
• 金额: $ 15.75万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-11 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286538
• 关键词: Address; Adipose tissue; Agonist; Anti-Inflammatory Agents; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; CASP1 gene; Cells; Cytokine Degradation; Data; Development; Disease; Exhibits; Flow Cytometry; Genetic; Genetic Transcription; Growth; Hormones; Immune; Immune response; Immune system; Immunity; Immunofluorescence Microscopy; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Insulin; Knock-in Mouse; Leucocytic infiltrate; Life; Link; Lung; Lung Inflammation; Lung infections; Macrophage Activation; Mediating; Metabolic; Metabolism; Microbe; Modeling; Mus; Mycoses; Pathology; Pathway interactions; Pharmacology; Production; Proteins; Publishing; Pulmonary Inflammation; RNA Binding; Regulation; Reporter; Reporting; Research; Resistance; Resolution; Role; System; Systems Biology; TIS11 protein; Therapeutic; Wild Type Mouse; Work; adiponectin; base; cytokine; immunopathology; in vivo; mRNA Stability; mRNA Transcript Degradation; macrophage; mortality; novel; novel therapeutics; pathogenic fungus; receptor; response; small molecule; therapeutic target

Abstract Due to widespread use of immune suppressive therapies, the incidence of life-threatening lung infections with fungal pathogens is increasing. Although protective immunity against Aspergillus fumigatus (Af) and other fungal pathogens is critical for host survival, excessive inflammation can also inhibit disease resolution. The potential to therapeutically target anti-inflammatory pathways to facilitate the resolution of fungal infection and associated pathology is understudied, primarily due to the difficulties of dissociating immune pathology from the pathologies directly linked to invasive fungal growth. We recently observed an increase in mortality, immune pathology, and antifungal inflammatory cytokine production in mice that lack the insulin-regulating cytokine adiponectin, thus establishing a novel link between the known anti-inflammatory role for adiponectin and control of excessive inflammation in fungal infection. Although most studies have focused on the role of adipose-derived adiponectin, our data suggest that adiponectin levels are regulated locally in the lung during IA. The role of non-adipose-tissue-derived adiponectin in controlling fungal infection- induced inflammation is unknown. Similarly, it is unclear whether macrophages and other immune cells are directly responsive to the immune-regulatory actions of adiponectin during IA. Using an unbiased, systems biology approach to study the impact of adiponectin during IA, we identified tristetraprolin (TTP) as a potential regulator. TTP is an RNA-binding and degrading protein known to regulate the production of multiple cytokines. Importantly, we have developed an experimental approach that allows us to separate immunopathology from fungal growth. With this approach we can specifically interrogate the mechanisms by which adiponectin regulates excessive pulmonary inflammation. Based on our results, our central hypothesis is that locally produced adiponectin acts directly on macrophages via AdipoR1/R2 engagement to activate TTP and subsequent cytokine degradation. In AIM 1, we will determine if adiponectin produced in non-adipose tissues such as the lungs is critical for protection from IA. In AIM 2, we will determine if adiponectin protects against inflammatory pathology in IA via AdipoR1/R2 on macrophages. We anticipate that these studies will delineate mechanisms of adiponectin-mediated inhibition of lung immune pathology. Our proposed work will identify novel targets with therapeutic potential and open new avenues of research in the development of detrimental immunity to infection.

抽象的 由于免疫抑制疗法的广泛使用，危及生命的肺部疾病的发生率 真菌病原体感染正在增加。虽然对曲霉有保护性免疫力 烟曲霉（Af）和其他真菌病原体对于宿主的生存至关重要，过度的炎症会 也抑制疾病的消退。治疗靶向抗炎途径的潜力 促进真菌感染的解决和相关病理学尚未得到充分研究，主要是由于 将免疫病理学与与侵袭性直接相关的病理学分开的困难 fungal growth.我们最近观察到死亡率、免疫病理学和抗真菌药物的增加 缺乏胰岛素调节细胞因子脂联素的小鼠产生炎症细胞因子，因此 在已知的脂联素抗炎作用和控制脂联素之间建立了新的联系 真菌感染引起的过度炎症。尽管大多数研究都集中在 脂肪来源的脂联素，我们的数据表明脂联素水平在体内受到局部调节 lung during IA.非脂肪组织来源的脂联素在控制真菌感染中的作用- 引起的炎症尚不清楚。同样，目前还不清楚巨噬细胞和其他免疫细胞是否 IA 期间，细胞对脂联素的免疫调节作用有直接反应。使用 我们采用公正的系统生物学方法来研究 IA 期间脂联素的影响 三四脯氨酸（TTP）作为潜在的调节剂。 TTP 是一种已知的 RNA 结合和降解蛋白 调节多种细胞因子的产生。重要的是，我们开发了一个实验性的 该方法使我们能够将免疫病理学与真菌生长分开。 With this approach we can specifically interrogate the mechanisms by which adiponectin regulates excessive pulmonary 炎。根据我们的结果，我们的中心假设是本地产生的脂联素 通过 AdipoR1/R2 接合直接作用于巨噬细胞，激活 TTP 和后续 cytokine degradation.在 AIM 1 中，我们将确定脂联素是否在非脂肪组织中产生 例如肺部对于预防 IA 至关重要。在 AIM 2 中，我们将确定脂联素是否可以保护 通过巨噬细胞上的 AdipoR1/R2 对抗 IA 中的炎症病理。 We anticipate that these 研究将阐明脂联素介导的肺部免疫病理抑制机制。我们的 拟议的工作将确定具有治疗潜力的新靶标，并开辟新的途径 研究针对感染的有害免疫的发展。