Nano and Microscale Molecular Machines for Innate Immune Sensing of Candida

用于念珠菌先天免疫传感的纳米和微型分子机器

• 批准号: 8984585
• 负责人: AARON KURT NEUMANN
• 金额: $ 42.04万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8984585
• 关键词: Actins; Active Biological Transport; Adopted; Affect; Antifungal Agents; Automobile Driving; Bacteria; Binding; Binding Sites; Bioinformatics; Biological Assay; Biology; Biophysics; C-Type Lectins; Candida; Candida albicans; Candidiasis; Caring; Cell Wall; Cell membrane; Communicable Diseases; Data; Dendritic Cells; Dendritic cell activation; Dengue; Detection; Development; Discrimination; Disease; Disseminated candidiasis; Elements; Event; Genus Mycobacterium; Geometry; Glucans; Goals; Host Defense; Human; Image; Imaging technology; Immune; Immunity; Immunologic Surveillance; Immunotherapeutic agent; Individual; Infection; Integrin Binding; Kinetics; Lateral; Lead; Leishmania; Leukocytes; Life; Ligands; Lipids; Macrophage-1 Antigen; Mannans; Masks; Mathematics; Measurement; Measures; Mediating; Membrane; Membrane Lipids; Methods; Mission; Modeling; Molecular Machines; Mycoses; Nanostructures; National Institute of Allergy and Infectious Disease; Natural Immunity; PTPRC gene; PTPRJ gene; Parasites; Patients; Pattern; Pattern recognition receptor; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Polysaccharides; Process; Public Health; Research; Resolution; Role; Sepsis; Signal Transduction; Site; Structure; Surface; Testing; Variant; Virus; Work; analytical method; base; biophysical techniques; cost; crosslink; dectin 1; design; fluorescence imaging; imaging modality; immune activation; immunogenic; immunogenicity; innovation; insight; microbial; mortality; nano; nanobiology; nanoscale; nanostructured; new therapeutic target; novel therapeutics; pathogen; physical process; public health relevance; quantitative imaging; receptor; response; segregation; sensor; spatiotemporal

 DESCRIPTION (provided by applicant): During innate immune recognition of Candida, the organization of cell wall ligands and pattern recognition receptors is an important determinant of successful immune activation. The long-term goal of our research is to achieve a deeper understanding of the physical processes of receptor-ligand engagement that govern activation vs. evasion during innate immune fungal recognition. Our central hypothesis in this project is that nanoscale organization of immunogenic cell wall β-glucan and its receptor Dectin-1 provides a mechanistic basis for Dectin-1 signal initiation, and that spatiotemporal orchestration of antifungal is key to achieving adequate Dectin-1 responses. We anticipate that this work will provide mechanistic insight into how fungal pathogens conceal immunogenic ligands in attempt to escape detection and how pattern recognition receptors are coordinated to generate effective innate immunity against Candida. Grounded in previous results and our strong preliminary data, we will pursue this objective in three Specific Aims. In Aim 1, we will test the hypothesis that β glucan "masking" in Candida species minimizes nanoscale exposure geometry of this immunogenic ligand to evade immune recognition. Our approach will involve nanoscopic measurements of β-glucan exposure and assays to assess the functional significance of β-glucan exposure geometry. In Aim 2, we will test the hypothesis that Dectin-1 nanodomain rearrangements upon glucan engagement drive a process of nanoscale segregation from regulatory phosphatases that is stabilized by lipid domain separation. In Aim 3, we will test the hypothesis that mannan/DC-SIGN interactions drive signaling that coordinates long-range active transport of Dectin-1 into host-pathogen contacts. This recruitment process is especially important for Dectin-1 to efficiently find sparse glucan exposures, leading to DC activation. This application features innovative application of high-resolution imaging technologies and quantitative image analytical methods to an important problem in infectious disease. Our studies will move the field beyond current models of fungal recognition mechanisms that are limited by lack of information on the nanoscopic scale, allowing a more detailed and accurate understanding of the physical mechanisms of innate immunity against Candida species pathogens and how they may evade immunity. This project joins the PI's demonstrated expertise in fungal immunity, membrane biophysics and quantitative fluorescence imaging together with an interdisciplinary team that brings additional expertise in surface fabrication methods, nanobiology, mathematics and image bioinformatics. We anticipate that our work will advance the field through fundamentally new discoveries in fungal immunity and new therapeutic strategies for Candidiasis.

 描述（由适用提供）：在念珠菌的先天免疫识别过程中，细胞壁配体和模式识别受体的组织是成功免疫反应的重要确定。我们研究的长期目标是更深入地理解受体 - 配体参与的物理过程，该过程在先天免疫识别过程中控制了激活与进化。我们在该项目中的中心假设是，免疫原性细胞壁β-葡聚糖及其受体Dectin-1的纳米级组织为Dectin-1信号启动提供了机械基础，并且抗真菌的时空管弦乐是实现足够的Dectin-1反应的关键。我们预计，这项工作将提供机械洞察力，了解真菌病原体如何掩盖免疫原性的配体以逃避检测，以及如何协调模式识别受体以产生有效的先天免疫学对念珠菌。基于先前的结果和我们强大的初步数据，我们将以三个特定目标追求这一目标。在AIM 1中，我们将测试β的假设 念珠菌物种中的葡聚糖“掩盖”可最大程度地减少这种免疫原性配体的纳米级暴露几何形状，以逃避免疫识别。我们的方法将涉及β-葡聚糖暴露的纳米镜测量，并主张β-葡聚糖暴露几何形状的功能意义。在AIM 2中，我们将检验以下假设：葡聚糖互动时Dectin-1纳米域重排驱动纳米级分离的过程，从脂质结构域分离稳定的调节磷酸酶。在AIM 3中，我们将检验以下假设：Mannan/DC-Sign相互作用驱动信号传导，该信号将Dectin-1的长距离主动转运置于宿主 - 病原体接触中。对于Dectin-1有效地发现稀疏的葡萄糖暴露，导致直流激活，这种募集过程尤为重要。该应用程序具有高分辨率成像技术的创新应用和定量图像分析方法在传染病中的重要问题上。我们的研究将使该领域超出当前的真菌识别机制模型，这些模型受纳米尺度上缺乏信息的限制，从而使对念珠菌物种病原体的先天免疫学的物理机制以及如何逃避免疫学的物理机制有了更详细，更准确的了解。该项目与PI在真菌免疫学，膜生物物理学和定量荧光成像方面展示了专业知识，以及一个跨学科团队，该团队在表面制造方法，纳米生物学，数学和图像生物信息学方面带来了更多专业知识。我们预计，我们的工作将通过真菌免疫和念珠菌病的新治疗策略的根本新发现来推进这一领域。