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: 10359102
• 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/10359102
• 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; Lateral; Lead; Leukocytes; Ligands; Lipids; Mediating; Modeling; Molecular; Mus; Mycoses; Optics; Oxygenases; Paracrine Communication; Pathway interactions; Patients; Pattern; Phagocytes; Pharmacologic Substance; Positioning Attribute; Process; Prostaglandin-Endoperoxide Synthase; Regulation; Reporter; Reporter Genes; Role; Series; Severities; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Virulence; Visual; Work; Zebrafish; analog; antagonist; base; data communication; defense response; design; fungus; human disease; improved; in vivo; insight; macrophage; 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 由烟曲霉菌引起的侵袭性曲霉病(IA)的特征是丝状菌丝不受控制 生长到宿主组织深处，是免疫低下患者的一种致命疾病，死亡率高达 高达90%。如此高的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，该系统介导了入侵菌丝 生长和吞噬细胞的激活。基于强大的初步数据，这一通信系统由以下部分组成 由特定真菌和宿主G识别的结构相似的真菌和宿主配体(例如氧脂) 蛋白偶联受体(GPCRs)。真菌和宿主氧脂相反地作用于调节真菌的生长。 和白细胞功能。我们假设真菌和宿主氧磷脂是跨王国的分子类似物 该信号通过特定的GPCR级联反应，诱导穿透性菌丝生长和操纵宿主防御 推动IA进展的反应。我们的数据不仅提供了对真核病原体和 它们的宿主在疾病期间直接相互交流，但也为 破译、操纵和控制这种有利于主机的通信系统的实验方法。 因此，我们将(1)确定氧合脂及其调节侵袭性的转录级联 分枝生长和(2)真菌和寄主相互识别的受体的特征 氧磷脂和这种认识的后果。Gpr是特别有利的治疗靶点。 设计(目前40%的药物以GPCR为靶点)。因此，在这项工作完成后，我们预计 我们将描绘出一种新的真菌-宿主配体-受体沟通语言 在人类疾病期间抑制丝状菌侵袭性生长的干预。