The role of fungal adhesins in the modulation of the innate immune response

真菌粘附素在调节先天免疫反应中的作用

基本信息

批准号：
7266394
负责人：
DUNCAN McNicol KUHN
金额：
$ 12.02万
依托单位：
WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7266394
关键词：
Accounting Actins Address Adherence Adhesions Adhesives Advisory Committees Affect Amino Acid Sequence Antibodies Antifungal Agents Attention Award Bacterial Adhesins Behavior Binding Biological Assay Bite Budgets Candida Candida albicans Candida glabrata Categories Cell Surface Proteins Cells Clinical Code Critiques Cytochalasin D Cytochalasins Data Depth Development Plans Diagnostic Doctor of Philosophy Effector Cell Environment Enzyme-Linked Immunosorbent Assay Epithelial Cells Event Experimental Designs Funding Gastrointestinal tract structure Gene Targeting Generations Genes Genetic Goals Grant Human Human Resources Imagery Immune Immune response Immune system Immunity Immunization In Vitro Infection Inflammatory Response Institutes Invasive Investigation Israel Just-in-time-concept Knowledge Lead Letters Lung Mammalian Cell Masks Mediating Mediator of activation protein Medical Research Membrane Membrane Proteins Messenger RNA Methods Modeling Modification Mus Mycoses National Institute of Allergy and Infectious Disease Natural Immunity Nature Organism Passive Immunization Pathogenesis Patients Peptide Sequence Determination Personal Satisfaction Phagocytosis Pharmaceutical Preparations Plasmids Population Principal Investigator Protein Array Protein Microarray Assay Protein Overexpression Proteins Receptor Cell Recommendation Regulation Reporting Research Research Ethics Committees Research Personnel Reverse Transcriptase Polymerase Chain Reaction Review Committee Role Saccharomyces cerevisiae Sampling Skin Specificity Staging Surface System Systemic infection Techniques Testing Text Therapeutic Thinking Time To specify Trypan Blue United States National Institutes of Health Urinary tract infection Vaccines Virulence Whole Organism Work Yeasts base career cytokine design fungus human disease immunoregulation improved in vivo in vivo Model insight macrophage mannose receptor medical schools monocyte novel outer surface lipoprotein pathogen programs protein distribution protein expression protein purification receptor research study response sound tool

项目摘要

DESCRIPTION (provided by applicant): The proposal is a 5-year program to enable an independent career in academic medical research, focusing on fungal pathogenesis and host response. This will occur in a collaborative environment at the Whitehead Institute and Harvard Medical School. Invasive fungal infections remain a threat to hospitalized patients. While C. albicans is the most significant pathogenic yeast, non-albicans species account for close to 50% of these infections. Initial interactions between fungi and innate immune cells present the first line of defense against these pathogens. Fungal surface adhesive proteins (adhesins) likely mediate these events. Despite the ubiquity of adhesins, and their binding to epithelial cells, little has been reported about interactions with the immune system. In addition, available data on host receptors cannot explain many aspects of fungal-host relationships. Macrophages are key components of the innate immunity, mediating effector cell and adaptive immunity. A novel C. glabrata adhesin, Epa1p, was recently shown to bind epithelial cells. My preliminary data indicates this is a novel, powerful, mediator of adherence to macrophages. Results indicate downstream effects include modulation of immune responses. I aim to understand how Epa1p mediates interactions with the innate immune system, leading to infection and immunomodulation. After identifying key binding behaviors, we will examine how this interaction affects macrophage mRNA and cytokine expression. To model human pathogenesis, I will utilize established murine models of infection. In addition, I will examine efficacy of both active (with Epa1p) and passive (with anti-Epa1p antibody) immunization in these models. Given the widespread distribution of these proteins in pathogenic fungi, the data will provide a paradigm for the behavior of fungal adhesins, applicable to a host of pathogens. This work will better define how fungal binding leads to immune modulation. This in turn will be expected to produce a) targets for novel antifungal agents, b) methods for active and passive immunization, c) potential diagnostic markers, and d) new avenues for immunomodulatory drugs.

描述（由申请人提供）：该提案是一个为期 5 年的计划，旨在实现学术医学研究的独立职业，重点关注真菌发病机制和宿主反应。这将在怀特海研究所和哈佛医学院的合作环境中进行。侵袭性真菌感染仍然对住院患者构成威胁。虽然白色念珠菌是最重要的致病酵母，但非白色念珠菌占这些感染的近 50%。真菌和先天免疫细胞之间的最初相互作用是针对这些病原体的第一道防线。真菌表面粘附蛋白（粘附素）可能介导这些事件。尽管粘附素无处不在，并且它们与上皮细胞结合，但关于其与免疫系统相互作用的报道却很少。此外，宿主受体的现有数据无法解释真菌-宿主关系的许多方面。巨噬细胞是先天免疫、介导效应细胞和适应性免疫的关键组成部分。最近发现一种新型光滑 C. glabrata 粘附素 Epa1p 可以结合上皮细胞。我的初步数据表明，这是一种新颖、强大的巨噬细胞粘附调节剂。结果表明下游效应包括免疫反应的调节。我的目标是了解 Epa1p 如何介导与先天免疫系统的相互作用，从而导致感染和免疫调节。在确定关键的结合行为后，我们将研究这种相互作用如何影响巨噬细胞 mRNA 和细胞因子的表达。为了模拟人类发病机制，我将利用已建立的小鼠感染模型。此外，我将检查这些模型中主动（使用 Epa1p）和被动（使用抗 Epa1p 抗体）免疫的效果。鉴于这些蛋白质在病原真菌中广泛分布，这些数据将为真菌粘附素的行为提供一个范例，适用于许多病原体。这项工作将更好地定义真菌结合如何导致免疫调节。这反过来又有望产生a）新型抗真菌药物的靶标，b）主动和被动免疫的方法，c）潜在的诊断标记物，以及d）免疫调节药物的新途径。