Regulation of Inflammatory Pathology in Invasive Aspergillosis

摘要 由于免疫抑制疗法的广泛使用，危及生命的肺部 感染真菌病原体的人数正在增加。虽然对曲霉的保护性免疫 烟霉菌(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 也会抑制疾病的分解。治疗靶向抗炎途径的可能性 促进真菌感染的解决和相关的病理学研究不足，主要是由于 将免疫病理学与直接与侵袭性有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。 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高血压之间建立新的联系 真菌感染时的过度炎症。尽管大多数研究都集中在细胞因子的作用上 脂肪来源的脂联素，我们的数据表明，脂联素水平在 心内直视手术期间的肺功能。非脂肪组织源性脂联素在控制真菌感染中的作用 诱导的炎症是未知的。同样，目前还不清楚巨噬细胞和其他免疫细胞 在IA期间，细胞直接对脂联素的免疫调节作用作出反应。使用 无偏见的系统生物学方法研究脂联素在IA期间的影响，我们发现 Tristetraprolin(TTP)作为一种潜在的调节剂。TTP是一种已知的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肺过度活动的机制 发炎。根据我们的结果，我们的中心假设是当地产生的脂联素 通过AdipoR1/R2结合直接作用于巨噬细胞，激活TTP及随后的 细胞因子的降解。在目标1中，我们将确定脂联素是否在非脂肪组织中产生 例如肺部对于保护人体免受IA的侵袭是至关重要的。在AIM 2中，我们将确定脂联素是否会保护 通过巨噬细胞上的AdipoR1/R2抗炎性病理改变。我们预计这些 研究将阐明脂联素介导的抑制肺免疫病理的机制。我们的 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 发展对感染的有害免疫的研究。

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.