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Regulation of Inflammatory Pathology in Invasive Aspergillosis

侵袭性曲霉病炎症病理学的调节

基本信息

批准号：
10427455
负责人：
Steven P Templeton
金额：
$ 18.9万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-11 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10427455
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 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

项目摘要

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.

摘要由于免疫抑制疗法的广泛使用，危及生命的肺结核的发病率增加，真菌病原体的感染正在增加。虽然对曲霉菌的保护性免疫烟曲霉（Af）和其他真菌病原体对宿主的生存至关重要，过度的炎症可以也抑制疾病消退。潜在的治疗目标抗炎途径，促进真菌感染和相关病理学的解决是研究不足，主要是由于将免疫病理学与直接与侵袭性疾病相关的病理学分离的困难，真菌生长我们最近观察到死亡率、免疫病理学和抗真菌药物的增加，在缺乏胰岛素调节细胞因子脂联素的小鼠中产生炎性细胞因子，在脂联素已知的抗炎作用和控制真菌感染的过度炎症。尽管大多数研究都集中在脂肪源性脂联素，我们的数据表明，脂联素水平在局部调节，在IA期间的肺。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未知。同样，目前还不清楚巨噬细胞和其他免疫细胞是否细胞在IA期间直接响应脂联素的免疫调节作用。使用无偏的，系统生物学方法来研究脂联素在IA期间的影响，我们确定 tristetraprolin（TTP）作为潜在的调节剂。TTP是已知的RNA结合和降解蛋白质，调节多种细胞因子的产生。重要的是，我们已经开发了一种实验性的这种方法使我们能够将免疫病理学与真菌生长分开。通过这种方法，我们可以特异性地询问脂联素调节过度肺动脉高压的机制，炎症基于我们的研究结果，我们的中心假设是本地产生的脂联素通过AdipoR 1/R2接合直接作用于巨噬细胞，以激活TTP和随后的细胞因子降解在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对于保护免受IA是至关重要的。在AIM 2中，我们将确定脂联素是否能保护通过巨噬细胞上的AdipoR 1/R2对抗IA中的炎症病理。我们预计，研究将描述脂联素介导的肺免疫病理学抑制的机制。我们拟议的工作将确定具有治疗潜力的新靶点，并开辟新的途径，研究对感染的有害免疫力的发展。