Bidirectional paracrine signaling in the establishment of invasive aspergillosis

侵袭性曲霉病建立中的双向旁分泌信号传导

基本信息

批准号：
10574521
负责人：
NANCY P KELLER
金额：
$ 47.2万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10574521
关键词：
Address Affect Antifungal Agents Aspergillosis Aspergillus Aspergillus fumigatus Automobile Driving Biochemical Biological Assay Calcium Communication Data Development Disease Disease Progression Equilibrium Family Filament Foundations Future G-Protein-Coupled Receptors Gene Fusion Genes Genetic Transcription Goals Growth Host Defense Immune response Immunocompromised Host In Vitro Integration Host Factors Kinetics Knowledge Language Leukocytes Ligands Lipids Macrophage Mediating Modeling Molecular Mus Mycoses Optics Oxygenases Paracrine Communication Pathway interactions Patients Pattern Penetration Phagocytes Pharmacologic Substance Positioning Attribute Predisposition Process Prostaglandin-Endoperoxide Synthase Regulation Reporter Reporter Genes Role Series Severities Signal Pathway Signal Transduction System Testing Therapeutic Therapeutic Intervention Tissues Virulence Visual With laterality Work Zebrafish analog antagonist defense response design fungus human disease improved in vivo insight microdevice migration mortality mouse model mutant neutrophil novel strategies pathogen receptor response small molecule small molecule inhibitor targeted treatment transcription factor transcriptome transcriptome sequencing

项目摘要

ABSTRACT Invasive aspergillosis (IA) caused by Aspergillus fumigatus is characterized by uncontrolled filamentous hyphal growth deep into host tissues and is a fatal disease of immunocompromised patients with mortality rates as high as 90%. This high mortality rate indicates the critical need for improved antifungal therapeutic strategies. We have uncovered a bidirectional lipid signaling system between the fungus and host that mediates invasive hyphal growth and phagocyte activation. Based on strong preliminary data, this communication system consists of structurally similar fungal and host ligands (e.g. oxylipins) that are recognized by specific fungal and host G protein coupled receptors (GPCRs). The fungal and host oxylipins work in opposition to regulate fungal growth and leukocyte functionality. We hypothesize that fungal and host oxylipins are cross-Kingdom molecular analogs that signal through specific GPCR cascades, inducing penetrating hyphal growth and manipulating host defense responses to drive IA progression. Our data not only provide new insight into how eukaryotic pathogens and their hosts communicate with one another directly during disease but also provide a new foundation for experimental approaches to decipher, manipulate, and control this communication system in favor of the host. Accordingly, we will (1) Identify the oxylipins and their transcriptional cascades that regulate invasive branching growth and (2) Characterize the receptors by which fungus and host recognize each other’s oxylipins and the consequences of this recognition. GPCR are particularly propitious targets for therapeutic design (40% of current pharmaceuticals target GPCR). Thus, upon completion of this work, we anticipate that we will have delineated a new fungal-host ligand-receptor communication language amenable to therapeutic intervention to inhibit filamentous invasive growth during human disease.

抽象的由烟曲霉引起的侵袭性曲霉菌病 (IA) 的特点是不受控制的丝状菌丝生长深入宿主组织，是免疫功能低下患者的致命疾病，死亡率很高高达 90% 的死亡率表明迫切需要改进抗真菌治疗策略。发现了真菌和宿主之间介导侵入性菌丝的双向脂质信号系统基于强有力的初步数据，该通信系统包括：结构相似的真菌和宿主配体（例如氧脂素），可被特定真菌和宿主 G 识别蛋白质偶联受体 (GPCR) 真菌和宿主氧脂质相反地调节真菌生长。我们勇敢地承认真菌和宿主氧脂质是跨界分子类似物。通过特定的 GPCR 级联发出信号，诱导穿透性菌丝生长并操纵宿主防御我们的数据不仅提供了关于真核病原体如何发展的新见解。它们的宿主在疾病期间直接相互交流，但也为破译、操纵和控制该通信系统以有利于宿主的实验方法。因此，我们将 (1) 鉴定调节侵入性的氧脂质及其转录级联反应。分支生长和（2）表征真菌和宿主相互识别的受体 oxylipins 和这种认识的结果是特别有利的治疗靶点。设计（目前 40% 的药物以 GPCR 为目标）。因此，在完成这项工作后，我们预计：我们将描绘出一种新的真菌-宿主配体-受体通讯语言，适合治疗在人类疾病期间抑制丝状侵入性生长的干预措施。