Interleukin-1a in fungal keratitis

真菌性角膜炎中的白介素-1a

• 批准号: 10405442
• 负责人: Bridget Ratitong
• 金额: $ 2.28万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405442
• 关键词: Address; Adoptive Transfer; Adrenal Cortex Hormones; Antifungal Agents; Aspergillus; Aspergillus fumigatus; Biogenesis; Biology; Blindness; Blocking Antibodies; Bone Marrow; Bone Marrow Transplantation; CASP1 gene; Cell Death; Cells; Contact Lenses; Cornea; Corneal Opacity; Corneal Stroma; Cytokine Signaling; Data; Disease; Environment; Epithelial Cells; Equilibrium; Exhibits; Extravasation; Eye Injuries; Family; Fungal Spores; Fusarium; Genes; Goals; Golgi Apparatus; Human; Hyphae; IL8 gene; Imaging Techniques; Immune; Immune response; Immunocompromised Host; Impairment; Individual; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 alpha; Interleukin-1 beta; Interleukins; Keratitis; Lead; Left; Molds; Mus; Mycoses; Myeloid Cells; Neutrophil Infiltration; Neutrophilic Infiltrate; Pathogenesis; Pathogenicity; Pathway interactions; Play; Process; Production; Regulation; Reproduction spores; Research; Resistance; Role; Signal Transduction; Site; System; Testing; Therapeutic Intervention; Tissues; Visual impairment; base; corneal epithelium; cytokine; exosome; extracellular vesicles; fungus; in vivo; inhibitor; macrophage; nano-string; neutrophil; new therapeutic target; pathogen; recruit; response; targeted treatment; transcriptomics; treatment response

PROJECT SUMMARY/ABSTRACT: Fungal keratitis is an infection of the corneas by pathogenic fungal species that is notoriously resistant to treatment and could lead to permanent blindness. Conidia (fungal spores) are ubiquitous in the environment and can infect healthy individuals following ocular trauma or unsanitary contact lens use. Once in the corneal stroma, conidia germinate resulting in rapid hyphae formation and tissue infiltration. Neutrophils are the first cells recruited to the corneas, and play a critical role in the host response against infection. While they are necessary to eliminate fungi, neutrophils also contribute to severe tissue damage. Current treatment includes antifungal agents followed by corticosteroids to suppress the inflammatory response. However, if the pathogen persists, this could lead to rapid hyphae invasion in the absence of an immune response. Therefore, there is a need for a more targeted treatment for inflammation to better control the balance between fungal clearance and tissue damage. To address this issue, we used Nanostring gene array analysis to analyze inflammatory genes that might be up- or down-regulated in neutrophils responding to fungal keratitis. We found that sorted neutrophils from the corneas of Aspergillus-infected mice highly upregulated Interleukin-1α (IL-1α) by >10,000 fold compared to bone marrow neutrophils. IL-1α is a pro-inflammatory cytokine that is critical for various infections. It is released by corneal epithelial cells as an alarmin to initiate and amplify inflammation, and can indirectly recruit neutrophils. IL-1α secretion is independent of the ER/golgi transport system. Many aspects of its biogenesis, regulation, and secretion are not well understood. Based on preliminary data, I hypothesize that IL-1α plays a critical role in the immune response during fungal keratitis. In this proposal, I will address three aims to support my hypothesis: 1) determine the importance of neutrophil-derived IL-1α during the inflammatory stages of Aspergillus keratitis, 2) define the role of corneal epithelial cells-derived IL-1α during disease, and 3) dissect the mechanism for IL-1α secretion from live neutrophils. The proposed research will address many unknown aspects of IL-1α, corneal epithelial cells, and neutrophil biology in response to fungal keratitis to provide a better understanding of the inflammatory processes involved.

项目摘要/摘要： 真菌性角膜炎是致病真菌物种对角膜的感染，众所周知 进行治疗，并可能导致永久失明。分生孢子（真菌孢子）在环境中无处不在 并可以在使用眼外伤或不卫生的隐形眼镜后感染健康的个体。一旦进入角膜 基质，分生孢子发芽，导致菌丝快速形成和组织浸润。中性粒细胞是第一个 招募到角膜的细胞在宿主反应中起着至关重要的作用。当他们是 消除真菌所需的中性粒细胞还会导致严重的组织损伤。当前治疗包括 抗真菌剂和抗皮质类固醇抑制炎症反应。但是，如果病原体 持续存在，这可能会导致在没有免疫反应的情况下迅速的菌丝侵袭。因此，有一个 需要进行更有针对性的治疗以更好地控制真菌清除之间的平衡 和组织损伤。为了解决这个问题，我们使用纳米串基因阵列分析来分析炎症 在对真菌角膜炎反应的中性粒细胞中可能上调或下调的基因。我们发现那是分类的 来自曲霉菌感染小鼠角膜的中性粒细胞高度更新了白介素1α（IL-1α）> 10,000 与骨髓嗜中性粒细胞相比折叠。 IL-1α是一种促炎性细胞因子，对各种感染至关重要。它由角膜释放 上皮细胞作为启动和扩增炎症的警报细胞，并可以间接募集中性粒细胞。 IL-1α 分泌独立于ER/Golgi运输系统。其生物发生，调节和 分泌不太了解。根据初步数据，我假设IL-1α在 真菌性角膜炎期间的免疫反应。在此提案中，我将针对支持我的三个目标 假设：1）确定中性粒细胞衍生的IL-1α在炎症阶段的重要性 曲霉角膜炎，2）定义角膜上皮细胞衍生的IL-1α在疾病中的作用，3）剖析 来自活嗜中性粒细胞的IL-1α分泌的机制。拟议的研究将解决许多未知的 IL-1α，角膜上皮细胞和中性粒细胞生物学的各个方面响应真菌角膜炎，以提供 更好地了解所涉及的炎症过程。