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: 10356728
• 负责人: HAROLD M HOFFMAN
• 金额: $ 32.67万
• 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/10356728
• 关键词: Affect; Antifungal Agents; Antigen Presentation; Aspergillus; Binding; Biochemical; 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; Interleukin-1; Knockout Mice; Lectin; Leukocytes; Light; Mediating; Microbiology; 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; macrophage; 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，可以了解涉及的先天免疫途径 宿主对球虫剂的反应，Coccidioides是一种侵入性的致病真菌，导致美国年度20,000次感染。 只有1-2％的患者受感染的患者发展出严重且经常致死的形式，称为传播 影响大脑，骨骼和/或皮肤的球虫病，通常需要终身治疗抗真菌 药物预防死亡并减少发病率。确定感染患者进程的因素不是 已知，但许多患者可能存在先天免疫失调 决定。虽然我们已经对普通侵入性真菌的正常宿主反应学到了很多东西 诸如念珠菌和曲霉等病原体，关于球虫剂仍有很多值得了解的地方。 我们将利用一种多管齐下的方法，重点是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 该反应的分子水平，例如RNA转录调节和串扰，蛋白质翻译和 翻译后处理以及细胞功能和细胞 - 细胞相互作用。为了实现我们的目标，我们有 在UCSD建立了一个生物医学调查员联盟，并具有悠久的协作历史，但相对新 对球虫毒剂的兴趣共同兴趣，并且拥有超过40年研究球虫毒剂的专家。 目标1。定义dectin-1和抑制性siglecs调节人髓样细胞的机制 对球虫剂的反应。使用来自正常人类供体的髓样细胞，我们将表征人类 Coccidioides的Dectin-1识别调节基因表达程序。使用功能收益研究，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 Dectin-1信号通路中的多态性改变了对球虫剂的细胞免疫响应。 AIM 2。确定球虫下感染和炎症体中IL-1和IL-1的细胞来源 控制其处理和释放的依赖和独立的途径 使用来自球菌患者的人体血细胞，对照组或特定敲除小鼠的细胞挑战 随着杀死球球菌的杀伤，我们将检查并阐明炎性体和非 - 在宿主对球虫下感染的宿主反应中，炎性体介导的裂解和IL-1和IL-1的释放。 目标3。研究激活和抑制受体对白细胞间穿梭的贡献 球孢子内孢子。我们将通过激活和 小鼠和人类中性粒细胞，巨噬细胞和树突状细胞上的抑制受体。 这项工作的总体影响将提高我们对Coccidioides免疫增强响应的理解 并提高我们预测球霉症患者的结局的能力。