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: 9232989
• 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/9232989
• 关键词: Adaptive Immune System; 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; Foundations; Genes; Genetic Transcription; Goals; Hospitalization; Immune; Immune Cell Activation; Immune response; Immunity; Immunocompromised Host; Immunologic Memory; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Inherited; Innate Immune Response; 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; Prostaglandin Production; Recruitment Activity; Role; Sepsis; Signal Transduction; Site; Skin; Stimulus; System; T cell response; Testing; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; Treatment Efficacy; adaptive immune response; base; combat; design; experimental study; 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; 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(申请人提供)：真菌通常感染皮肤和粘膜。健康的人可以有效地控制这种感染；然而，在免疫功能低下的人和医院患者中，真菌感染可能成为全身性感染，在这一点上，它们与显著的发病率有关。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。拟议实验的前提是，了解控制健康个体真菌感染的炎症过程的激活机制将揭示可用于治疗易感患者的念珠菌病的新的治疗靶点。在这里，我们试图揭示天然免疫和非免疫细胞中激活的T细胞核因子(NFAT)是如何诱导针对念珠菌的保护性免疫反应，从而防止真菌的侵袭性传播和致死性系统性念珠菌病。炎症是对有害刺激的保护性血管反应，导致血管通透性增加，免疫细胞招募到感染部位以对抗入侵的微生物。先天免疫和组织特异性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，并导致保护性适应性免疫记忆的形成。NFAT转录因子家族最初与获得性免疫细胞的激活有关，但我们和其他人已经证明，在暴露于炎性刺激后，特别是在对真菌识别的反应中，NFAT通路在先天性免疫和非免疫细胞中也被有效地激活。NFAT激活的一个主要作用是诱导前列腺素(PG)E2和白细胞介素2(IL)-2的产生大幅增加，但这些分子浓度大幅上升的意义完全没有被探索过。我们的目标是验证这一假设，即在真菌感染的反应中，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，并形成保护性记忆。我们将使用小鼠模型来确定早期NFAT激活如何协调真菌的识别和破坏，如何将病原体有效地运输到引流淋巴结(DLN)，以及在抗真菌炎症反应中LN微结构的重塑(对适应性免疫细胞激活和长期保护非常重要)。这代表了一个新的、未被探索的研究领域，对深入了解炎症的复杂性具有重要意义。 这是一项强有力的任务，需要设计更好的预防和治疗成人和儿童念珠菌病的手段。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突破，并将产生对炎症生理学的更多了解。