Innate control of the inflammatory process during fungal infections

真菌感染期间炎症过程的先天控制

• 批准号: 9122779
• 负责人: Ivan Zanoni
• 金额: $ 44.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9122779
• 关键词: Address; Adult; Affect; Antifungal Agents; Architecture; Area; Biological; Blood Vessels; Candida; Candida albicans; Candidiasis; Cells; Child; Containment; Cyst; Data; Dendritic Cells; Development; Dinoprostone; Disseminated candidiasis; Excess Mortality; Exposure to; Family; Fibroblasts; Genes; Goals; Hospitalization; Immune; Immune Cell Activation; Immune response; Immune system; Immunity; Immunocompromised Host; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Inherited; Interleukin-2; Invaded; Investigation; Laboratories; Lead; Length; Length of Stay; Lymphocyte; Memory; Molecular; Morbidity - disease rate; Mucous Membrane; Mutation; Mycoses; Necrosis; Neutrophil Infiltration; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Peripheral; Permeability; Phase; Physiology; Play; Process; Production; Recruitment Activity; Role; Sepsis; Signal Transduction; Site; Skin; Stimulus; System; T cell response; T-Cell Activation; Testing; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; adaptive immunity; base; combat; design; fungus; improved; insight; lymph nodes; mast cell; member; microorganism; mortality; mouse model; neutrophil; new therapeutic target; novel; nuclear factors of activated T-cells; pathogen; prevent; public health relevance; repaired; research study; response; transcription factor

 DESCRIPTION (provided by applicant): Fungi usually infect the skin and mucosa. Healthy individuals can efficiently control such infections; however, in immunocompromised individuals and nosocomial patients, fungal infections may become systemic, at which point they are associated with significant morbidity. Candidiasis is the most common fungal infection, and is associated with prolonged hospital stays and high mortality rates. The premise underlying the proposed experiments is that understanding the mechanisms of activation of the inflammatory process that controls fungal infections in healthy individuals will reveal novel therapeutic target that can be used to treat candidiasis in susceptible patients. Here, we seek to uncover how activation of Nuclear Factor of Activated T cells (NFAT) in innate immune and non-immune cells induces protective immune responses against Candida, thus preventing invasive spread of the fungus and lethal systemic candidiasis. Inflammation is a protective vascular response to noxious stimuli that causes increased blood vessel permeability and recruitment of immune cells to the site of infection to combat the invading microorganism. Innate immune and tissue-specific non-immune cells regulate the development and potency of the inflammatory process via transcriptional and non-transcriptional responses, and lead to the formation of a protective adaptive immune memory. The NFAT family of transcription factors was originally associated with activation of adaptive immune cells; but we and others have demonstrated that the NFAT pathway is also potently activated in innate immune and non-immune cells following exposure to inflammatory stimuli, especially in response to fungal recognition. A major effect of NFAT activation is to induce a large increase in the production of prostaglandin (PG)E2 and interleukin (IL)-2, but the significance of the huge spike in the concentration of these molecules in response to fungi is totally unexplored. We aim to test the hypothesis that, in response to fungal infection NFAT is activated in innate immune and non-immune cells to regulate the inflammatory process, destruction of the invading pathogen, and formation of a protective memory. We will use mouse models to determine how early NFAT activation orchestrates fungal recognition and destruction, efficient transport of pathogen to the draining lymph node (dLN), and remodeling of LN microarchitecture (important for adaptive immune cell activation and long lasting protection) during anti-fungal inflammatory responses. This represents a new, unexplored area of investigation, with important implications for gaining insights into the complexity of inflammation driven immunity, and for addressing the excess mortality and the length and financial burden of hospitalization, which present a potent mandate for designing improved means of preventing and treating candidiasis in adults and children. We contend that clarification of the role of NFAT activation during the initial phases of the inflammatory process will provide a fundamental breakthrough for designing new strategies for treating fungal infection, and will yield a greater understanding of the physiology of inflammation.

 描述（由适用提供）：真菌通常会感染皮肤和粘膜。健康的个体可以有效控制这种感染；但是，在免疫功能低下的个体和医院患者中，真菌感染可能会成为系统性，此时它们与明显的发病率有关。念珠菌病是最常见的真菌感染，与长时间住院和高死亡率有关。提出的实验的前提是，了解健康个体中真菌感染的炎症过程的激活机制将揭示出可用于治疗易感患者的念珠菌病的新型治疗靶标。在这里，我们试图发现先天免疫和非免疫细胞中活化T细胞（NFAT）的核因子如何诱导保护性免疫反应，从而防止真菌的侵入性和炎症是对有害刺激的受保护的血管反应，从而导致了增加的血管渗透性和招募的受伤部位，以抑制受伤的部位的受伤性。微生物。先天免疫细胞和组织特异性的非免疫细胞通过转录和非转录反应调节炎症过程的发育和效力，并导致形成受保护的适应性免疫电池记忆。转录因子的NFAT家族最初与自适应免疫球的激活有关。但是我们和其他人已经证明，在暴露于炎症刺激后，NFAT途径也可能在先天免疫和非免疫细胞中激活，尤其是在响应真菌识别的情况下。 NFAT激活的主要作用是诱导前列腺素（PG）E2和白介素（IL）-2的产生大量增加，但是这些分子浓度巨大的峰值对真菌的浓度的重要性是完全出乎意料的。我们旨在检验以下假设：在对真菌感染的响应中，NFAT在先天免疫和非免疫细胞中被激活，以调节炎症过程，破坏入侵的病原体以及形成保护性记忆。我们将使用小鼠模型来确定早期NFAT激活如何策划真菌识别和破坏，病原体有效运输到排水淋巴结（DLN）（DLN）以及LN微体系结构的重塑（对于自适应免疫细胞激活和持久的保护和持久保护的重要性）。这代表了一个新的，意外的投资领域，对获得炎症复杂性的见解具有重要意义 驱动的免疫力，以及解决住院的过剩死亡率以及长度和经济燃烧，这赋予了设计改进的预防和治疗成人和儿童念珠菌病的方法的潜在任务。我们认为，阐明NFAT激活在炎症过程的初始阶段的作用将为设计治疗真菌感染的新策略提供根本的突破，并将对感染的生理学有更深入的了解。