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.

项目概要/摘要： 真菌性角膜炎是由病原真菌引起的角膜感染，众所周知，这种真菌具有很强的抗药性 分生孢子（真菌孢子）在环境中普遍存在。 一旦进入角膜，可能会在眼外伤或使用不卫生的隐形眼镜后感染健康人。 基质、分生孢子萌发，导致菌丝快速形成和中性粒细胞浸润。 细胞被招募到角膜，并在宿主抵抗感染的反应中发挥关键作用。 中性粒细胞是消除真菌所必需的，但它也会导致严重的组织损伤。目前的治疗包括。 然而，如果病原体存在，则使用抗真菌药物，然后使用皮质类固醇来抑制炎症反应。 如果持续存在，这可能会导致在没有免疫反应的情况下快速菌丝入侵。 需要更有针对性的炎症治疗，以更好地控制真菌清除之间的平衡 为了解决这个问题，我们使用纳米线基因阵列分析来分析炎症。 我们发现中性粒细胞对真菌性角膜炎的反应可能上调或下调的基因。 曲霉感染小鼠角膜中的中性粒细胞将白介素 1α (IL-1α) 高度上调超过 10,000 与骨髓中性粒细胞相比呈倍数。 IL-1α 是一种促炎细胞因子，对各种感染至关重要，由角膜释放。 上皮细胞作为警报素启动和放大炎症，并可以间接招募中性粒细胞。 其生物发生、调节和代谢的许多方面均独立于 ER/高尔基体转运系统。 根据初步数据，我认为 IL-1α 在其中发挥着关键作用。 真菌性角膜炎期间的免疫反应 在本提案中，我将提出三个目标来支持我的观点。 假设：1）确定中性粒细胞来源的IL-1α在炎症阶段的重要性 曲霉菌性角膜炎，2) 定义角膜上皮细胞衍生的 IL-1α 在疾病期间的作用，以及 3) 解剖 活中性粒细胞分泌 IL-1α 的机制拟议的研究将解决许多未知的问题。 IL-1α、角膜上皮细胞和中性粒细胞生物学方面对真菌性角膜炎的反应提供了 更好地了解所涉及的炎症过程。