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: 10450028
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450028
• 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; 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; organ transplant recipient; 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.

项目总结/摘要 侵袭性真菌感染与异常高的死亡率相关，通常超过80%， 由于免疫功能低下患者的快速增长，发病率增加。曲霉 烟曲霉是侵袭性真菌感染的主要原因之一， 从皮肤和软组织到播散性感染。在接受造血或实体治疗的患者中， 器官移植后，大约10%的人会患上侵袭性曲霉病。持续的高死亡率 尽管抗真菌治疗突出了我们目前抗真菌设备的不足， 免疫系统在清除感染中的作用。有效的真菌免疫是由先天性 免疫识别的复合物，碳水化合物真菌细胞壁，然后细胞因子的生产，活性氧 产生、吞噬和杀死病原体。真菌碳水化合物抗原的谱显示在 真菌细胞壁决定了参与的模式识别受体，并影响保护性或非保护性受体的作用。 产生保护性反应。在此申请中，候选人提出K 08指导临床科学家 研究职业发展奖授予，将表征巨噬细胞的分子机制， 中性粒细胞对A.烟曲霉碳水化合物，半乳甘露聚糖（GALM）和半乳糖胺半乳聚糖 （GAG）。为了确定参与对这些碳水化合物反应的亚细胞途径， 将使用由单一纯化的碳水化合物组成的颗粒（FLP），所述碳水化合物稳定地涂覆聚苯乙烯珠。 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GALM的识别和应答中， 特异性地探测Dectin-2和下游效应物Syk在细胞因子产生、吞噬作用 和吞噬体成熟。具体目标2旨在确定介导巨噬细胞 和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， 对GAG介导的免疫抑制至关重要的受体，并定义了GAG在细胞因子产生中的作用， ROS生成和吞噬作用。候选人是一名医生-科学家，并已完成临床 在联合马萨诸塞州总医院和布里格姆和妇女传染病奖学金 程序.她在真菌分子生物学方面有研究经验， 定义与人类病原体的毒力和多样性产生有关的信号通路， 念珠菌和隐球菌。她的总体职业目标是成为一名独立的调查员，能够探索 宿主-病原体界面因此，这项职业发展补助金概述了一个教学，指导和科学 研究计划，将提供必要的培训，在宿主免疫学必要的研究动态 宿主和病原体之间的相互作用，并成为一个富有成效的独立的医生科学家。

项目成果

Single Cell Transcriptomes, Lineage, and Differentiation of Functional Airway Microfold Cells.

功能性气道微褶皱细胞的单细胞转录组、谱系和分化。

• DOI: 10.1101/2023.08.06.552176
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Surve,ManaleeV;Lin,Brian;Reedy,JenniferL;Crossen,ArianneJ;Xu,Anthony;Klein,BruceS;Vyas,JatinM;Rajagopal,Jayaraj
• 通讯作者: Rajagopal,Jayaraj