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

• 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
• 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

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.

摘要 由烟曲霉引起的侵袭性曲霉病（IA）的特征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，死亡率高达 为90%。这种高死亡率表明迫切需要改进抗真菌治疗策略。我们 已经发现了真菌和宿主之间的双向脂质信号系统，该系统介导侵入性菌丝 生长和吞噬细胞活化。根据强有力的初步数据，该通信系统包括： 结构相似的真菌和宿主配体（如氧脂素），可被特定的真菌和宿主G 蛋白偶联受体（GPCR）。真菌和宿主的氧化脂蛋白在调节真菌生长方面起着相反的作用 和白细胞功能。我们假设真菌和宿主氧化脂是跨界的分子类似物 通过特异性GPCR级联信号，诱导穿透性菌丝生长并操纵宿主防御 推动IA进展的反应。我们的数据不仅为真核病原体和 它们的宿主在疾病期间直接相互交流，但也为疾病提供了新的基础。 实验方法来破译，操纵和控制这个有利于主机的通信系统。 因此，我们将（1）确定氧化脂质及其转录级联调节侵入性 分枝生长和（2）表征真菌和宿主识别彼此的受体 oxlipins和这种认识的后果。GPCR是用于治疗的特别有利的靶标。 设计（目前40%的药物以气相化学还原为目标）。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， 干预以抑制人类疾病期间的丝状侵入性生长。