Innate Immune Response to Aspergillus fumigatus Cell Wall Carbohydrates

对烟曲霉细胞壁碳水化合物的先天免疫反应

• 批准号: 10212945
• 负责人: Jennifer Lynne Reedy
• 金额: $ 19.98万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-21 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212945
• 关键词: Affect; Antifungal Agents; Antifungal Therapy; Antigen Presentation; Antigens; Aspergillosis; Aspergillus fumigatus; Award; Biological Assay; Candida; Carbohydrate Biochemistry; Carbohydrates; Cell Wall; Clinical; Communicable Diseases; Complex; Critical Pathways; Cryptococcus; Data; Defect; Disease; Fellowship; Functional disorder; Fungal Antigens; General Hospitals; Generations; Glucans; Goals; Grant; Growth; Health; Hematopoietic; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunocompromised Host; Immunology; Immunosuppression; Incidence; Individual; Infection; Inflammatory; Inflammatory Response; Innate Immune Response; Innate Immune System; K-Series Research Career Programs; Macrophage-1 Antigen; Massachusetts; Measurement; Mediating; Mentors; Mentorship; Molecular; Molecular Biology; Morbidity - disease rate; Mycoses; Organ Transplantation; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Pattern recognition receptor; Phagocytosis; Phagosomes; Pharmacology; Physicians; Play; Polystyrenes; Population; Prevalence; Process; Production; Protein-Carbohydrate Interaction; Proteins; Proteomics; Reactive Oxygen Species; Research; Research Personnel; Role; Scientist; Sentinel; Signal Pathway; Signal Transduction; Skin Tissue; Solid; Technology; Training; Training Programs; Transplant Recipients; Virulence; Woman; carbohydrate binding protein; career; career development; cell type; chemical conjugate; cytokine; dectin 1; experience; fungus; galactomannan; galactosaminogalactan; human pathogen; immunomodulatory therapies; improved outcome; macrophage; mortality; mouse dectin-2; mutant; neutrophil; novel; novel therapeutic intervention; particle; pathogen; pathogenic fungus; programs; receptor; recruit; response; soft tissue

Project Summary/Abstract Invasive fungal infections are associated with exceptionally high mortality rates often exceeding 80%, and are increasing in incidence due to a rapidly growing population of immunocompromised patients. Aspergillus fumigatus is one of the leading causes of invasive fungal infections and causes a spectrum of diseases ranging from skin and soft tissue to disseminated infections. Amongst patients that received hematopoietic or solid- organ transplants, approximately 10% will develop invasive aspergillosis. The persistently high mortality rates despite antifungal therapy highlights the deficiencies in our current antifungal armamentarium and the critical role that the immune system plays in the clearance of infections. Effective fungal immunity is initiated by innate immune recognition of the complex, carbohydrate fungal cell wall followed by cytokine production, ROS generation, phagocytosis and killing of pathogens. The profile of fungal carbohydrate antigens displayed on the fungal cell wall dictates the pattern recognition receptors engaged and influences whether a protective or non- protective response is generated. In this application, the candidate proposes a K08 Mentored Clinical Scientist Research Career Development Award grant that will characterize molecular mechanisms of macrophages and neutrophil response to the A. fumigatus carbohydrates, galactomannan (GALM) and galactosaminogalactan (GAG). To define the subcellular pathways involved in the response to these carbohydrates, novel fungal like particles (FLP) composed of single purified carbohydrates stably coating polystyrene beads will be utilized. Preliminary data suggests that Dectin-2 is a receptor for GALM. Specific Aim 1 will define the role of Dectin-2 in macrophages and neutrophil recognition and response to both soluble and cell wall associated GALM, specifically probing the role of Dectin-2 and the downstream effector Syk in cytokine production, phagocytosis, and phagosomal maturation. Specific Aim 2 seeks to define the molecular pathways that mediate macrophage and neutrophil responses to soluble and cell wall-associated GAG. This aim will define signaling pathways and receptors critical for GAG mediated immunosuppression and define the role of GAG in cytokine production, ROS generation, and phagocytosis. The candidate is a physician-scientist and has completed a clinical fellowship in the combined Massachusetts General Hospital and Brigham and Women's Infectious Diseases Program. She has research experience in fungal molecular biology having devoted her graduate training to defining signaling pathways involved in virulence and the generation of diversity in the human pathogens, Candida and Cryptococcus. Her overall career goal is to be an independent investigator capable of probing the host-pathogen interface. Therefore this career development grant outlines a didactic, mentoring, and scientific research plan that will provide the necessary training in host immunology necessary to study the dynamic interplay between host and pathogen and become a productive independent physician-scientist.

项目摘要/摘要 侵袭性真菌感染与极高的死亡率有关，通常超过80%，而且 由于免疫功能低下患者的人口迅速增长，发病率不断上升。曲霉菌 烟曲霉菌是侵袭性真菌感染的主要原因之一，可引起一系列疾病 从皮肤和软组织到播散性感染。在接受造血或固体治疗的患者中- 器官移植，大约10%会发展成侵袭性曲霉病。居高不下的死亡率 尽管抗真菌治疗突出了我们目前抗真菌治疗的不足和关键 免疫系统在清除感染方面所起的作用。有效的真菌免疫是由先天启动的 免疫识别复杂的碳水化合物真菌细胞壁，随后产生细胞因子，ROS 病原体的产生、吞噬和杀灭。上显示的真菌碳水化合物抗原的概况 真菌细胞壁决定了模式识别受体的参与，并影响保护性或非保护性 产生保护性反应。在本申请中，候选人推荐一名K08临床科学家导师 研究事业发展奖授予将表征巨噬细胞和 中性粒细胞对烟曲霉碳水化合物、半乳甘露聚糖(GALM)和半乳糖氨基半乳糖的反应 (插嘴)。为了确定参与对这些碳水化合物的反应的亚细胞途径，新型真菌如 将使用由稳定包覆聚苯乙烯珠粒的单一纯化碳水化合物组成的颗粒(FLP)。 初步数据表明Dectin-2是GALM的受体。具体目标1将定义Dectin-2的作用 在巨噬细胞和中性粒细胞对可溶性和细胞壁相关的Galm的识别和反应中， 特别是探讨Dectin-2及其下游效应蛋白Syk在细胞因子产生、吞噬、 吞噬小体成熟。特异性目标2试图定义介导巨噬细胞的分子途径 中性粒细胞对可溶性和细胞壁相关的GAG的反应。这一目标将定义信号通路和 GAG介导的免疫抑制的关键受体，并确定GAG在细胞因子产生中的作用， ROS生成和吞噬作用。应聘者是一名内科科学家，并已完成临床 马萨诸塞州总医院与布里格姆和妇女传染病联合医院的奖学金 程序。她在真菌分子生物学方面有研究经验，她的研究生培训致力于 定义涉及毒力和人类病原体多样性产生的信号通路， 念珠菌和隐球菌属。她的整个职业目标是成为一名能够调查 宿主-病原体界面。因此，这份职业发展基金概述了一种说教、指导和科学的 研究计划将提供研究动态所需的宿主免疫学方面的必要培训 宿主和病原体之间的相互作用，并成为一名富有成效的独立内科科学家。