Innate immune mechanisms of the host response to Coccidioides

宿主对球孢子菌反应的先天免疫机制

• 批准号: 10554376
• 负责人: HAROLD M HOFFMAN
• 金额: $ 29.79万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-24 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554376
• 关键词: Affect; Antifungal Agents; Antigen Presentation; Aspergillus; Binding; Biochemical; Biological; Blood Cells; Brain; Candida; Cell Communication; Cell physiology; Cells; Cessation of life; Clinical; Clinical Immunology; Coccidioides; Coccidioides immitis; Coccidioidomycosis; Collaborations; Communicable Diseases; Data; Dendritic Cells; Disease; Disease model; Equilibrium; Gene Expression; Genes; Genetic Determinism; Genetic Polymorphism; Genetic Transcription; Genetic study; Goals; Human; Immune; Immune System Diseases; Immune response; Immunity; Immunogenetics; Immunoglobulins; Immunologics; Infection; Inflammasome; Inflammation; Inflammatory; Innate Immune Response; Knockout Mice; Learning; Lectin; Leukocytes; Macrophage; Mediating; Molecular; Morbidity - disease rate; Mus; Mycoses; Myeloid Cells; Natural Immunity; Natural Killer Cells; Outcome; Pathway interactions; Patients; Pattern Recognition; Play; Predisposition; Process; Production; Proteins; RNA; Recording of previous events; Research Personnel; Risk; Role; Sialic Acids; Signal Pathway; Signal Transduction; Skin; Source; Structure; Transcriptional Regulation; Translations; Virulence; Virulence Factors; Work; adaptive immune response; adverse outcome; base; bone; chemokine; collaborative approach; cytokine; dectin 1; experience; gain of function; improved; in vivo; innate immune mechanisms; innate immune pathways; interest; mouse model; neutrophil; new therapeutic target; outcome prediction; pathogen; pathogenic fungus; prevent; prognostic indicator; programs; receptor; receptor binding; recruit; response; screening; sialic acid binding Ig-like lectin; stem

Summary – Project 1 Project 1 is a new collaborative approach to understand the innate immune pathways involved in the host response to Coccidioides, an invasive pathogenic fungus resulting in 20,000 infections in the US annually. Only 1-2% of patients infected develop a severe and frequently lethal form, known as disseminated coccidiomycosis which affects brain, bones, and/or skin and usually requires lifelong therapy with anti-fungal drugs to prevent death and reduce morbidity. The factors determining the course of infected patients are not known, but it is likely that there is innate immune dysregulation in many of these patients that is genetically determined. While we have learned a great deal about the normal host response to common invasive fungal pathogens such as Candida and Aspergillus, there still remains much to be learned about Coccidioides. We will utilize a multi-pronged approach focusing on each major step of the innate immune response including 1) pattern recognition 2) cytokine responses and 3) pathogen processing, and on the specific molecular levels of this response such as RNA transcriptional regulation and cross-talk, protein translation and post-translation processing, as well as cell function and cell-cell interaction. To accomplish our goals, we have built a coalition of biomedical investigators at UCSD with a long history of collaboration, but a relatively new shared interest in Coccidioides and an expert with more than 40 years of experience studying Coccidioides. Aim 1. Define the mechanisms by which Dectin-1 and inhibitory Siglecs regulate human myeloid cell responses to coccidioides. Using myeloid cells from normal human donors we will characterize how human dectin-1 recognition of Coccidioides regulates gene expression programs. Using gain-of-function studies we will determine how iSiglec engagement inhibits Dectin-1 signaling. Finally, we will determine how human polymorphisms in Dectin-1 signaling pathways alter the cellular immune response to Coccidioides. Aim 2. Identify the cellular source of IL-1 and IL-1 in coccidioides infection and the inflammasome dependent and independent pathways controlling their processing and release Using human blood cells from cocci patients and controls or cells from specific knockout mice challenged with killed Coccidioides spherules, we will examine and shed light on the role of inflammasome and non- inflammasome mediated cleavage and release of IL-1 and IL-1 in the host response to Coccidioides infection. Aim 3. Investigate the contribution of activating and inhibitory receptors to inter-leukocyte shuttling of coccidioides endospores. We will investigate the control of Coccidioides endospore shuttling by activating and inhibitory receptors on mouse and human neutrophils, macrophages, and dendritic cells. The overall impact of this work will improve our understanding of the immune response to Coccidioides and improve our ability to predict outcomes in patients with coccidiomycosis.

摘要 – 项目 1 项目 1 是一种新的协作方法，旨在了解参与免疫反应的先天免疫途径。 球孢子菌是一种侵入性致病真菌，每年在美国导致 20,000 例感染。 只有 1-2% 的感染患者会出现严重且常常致命的形式，即播散性感染 影响大脑、骨骼和/或皮肤的球孢子菌病，通常需要终生抗真菌治疗 预防死亡和降低发病率的药物。决定感染患者病程的因素不是 已知，但这些患者中的许多人可能存在先天性免疫失调，这是遗传性的 决定。虽然我们已经了解了大量关于常见侵入性真菌的正常宿主反应 尽管与念珠菌和曲霉菌等病原体相比，球孢子菌仍有很多需要了解的地方。 我们将采用多管齐下的方法，重点关注先天免疫反应的每个主要步骤 包括 1) 模式识别 2) 细胞因子反应和 3) 病原体加工，以及特定的 这种反应的分子水平，如 RNA 转录调控和串扰、蛋白质翻译和 翻译后加工，以及细胞功能和细胞间相互作用。为了实现我们的目标，我们有 在加州大学圣地亚哥分校建立了一个生物医学研究人员联盟，该联盟具有悠久的合作历史，但相对较新 对球孢子菌有着共同的兴趣，并且是一位拥有 40 多年研究球孢子菌经验的专家。 目标 1. 明确 Dectin-1 和抑制性 Siglecs 调节人骨髓细胞的机制 对球孢子菌的反应。使用来自正常人类捐赠者的骨髓细胞，我们将描述人类如何 dectin-1 对球孢子菌的识别可调节基因表达程序。通过功能获得研究，我们将 确定 iSiglec 参与如何抑制 Dectin-1 信号传导。最后，我们将确定人类如何 Dectin-1 信号通路的多态性改变了对球孢子菌的细胞免疫反应。 目标 2. 鉴定球孢子菌感染和炎症小体中 IL-1 和 IL-1 的细胞来源 控制其加工和释放的依赖和独立途径 使用来自球菌患者和对照的人血细胞或来自受攻击的特定基因敲除小鼠的细胞 通过杀死球孢子菌小球，我们将检查并阐明炎症小体和非炎症小体的作用 在球孢子菌感染的宿主反应中，炎症小体介导的 IL-1 和 IL-1 的裂解和释放。 目标 3. 研究激活和抑制受体对白细胞间穿梭的贡献 球孢子内生孢子。我们将通过激活和研究球孢子菌内生孢子穿梭的控制 小鼠和人类中性粒细胞、巨噬细胞和树突状细胞的抑制性受体。 这项工作的总体影响将提高我们对球孢子菌免疫反应的理解 并提高我们预测球孢子菌病患者预后的能力。