Global analysis of circuitry governing fungal activation of host inflammation

控制宿主炎症真菌激活的电路的整体分析

• 批准号: 9505492
• 负责人: Teresa R. OMeara
• 金额: $ 16.09万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9505492
• 关键词: Address; Antifungal Agents; Apoptosis; Biological; Candida albicans; Candidate Disease Gene; Caspase; Cell Death; Cell Survival; Cell Wall; Cells; Collection; Cryptococcus neoformans; Cytolysis; Development; Drug resistance; Environment; Enzymes; Exposure to; Fungal Genes; Gene Expression; Genes; Genetic Transcription; Goals; Health; Human; Immune; Immune response; Immunocompromised Host; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Innate Immune System; Integration Host Factors; Interleukin-1 beta; Invaded; Macrophage Activation; Maps; Mediating; Medical; Mus; Mycoses; Pathway interactions; Phagocytes; Phagocytosis; Phagosomes; Pharmaceutical Preparations; Phenotype; Population; Portraits; Process; Proliferating; Research; Resistance development; Resolution; Rest; Signal Transduction; Therapeutic; Therapeutic Intervention; Toxic effect; Work; drug development; functional genomics; fungus; gene function; genome-wide; human disease; interdisciplinary approach; knock-down; macrophage; microbial; microorganism; mutant; neutrophil; new therapeutic target; novel therapeutics; pathogen; pathogenic fungus; programs; response; screening

Project Summary / Abstract Fungal pathogens take a devastating toll on human health worldwide, and fungal infections are on the rise due to the growing population of immunocompromised individuals. Treating fungal infections is extremely difficult, as fungi are closely related to humans and there are very few drugs that kill the fungus without host toxicity. With the emergence of drug resistance, the development of new therapeutics is now crucial. To address this unmet medical need and identify new targets for drug development, it is critical to uncover mechanisms that enable these pathogens to cause human disease. I have developed a powerful approach to study the front line of human defense against these fungal pathogens. Host innate immune cells recognize and engulf the invading pathogens, but the fungal cells are able to adapt and trigger immune cell death. I recently discovered that this immune cell death requires fungal cell wall remodeling and the NLRP3 inflammasome. However, the specific trigger and mechanisms involved remain enigmatic. Here, I propose an interdisciplinary approach to examine mechanisms by which fungi are able to induce host cell death, and the host pathways that are required for responding to the invading pathogen. Our global analyses of fungal gene expression, gene function and host immune responses will provide a high-resolution portrait of this host-pathogen interface, and reveal new targets for therapeutics to save human lives.

项目总结/摘要 真菌病原体对全世界的人类健康造成毁灭性的损失， 由于免疫功能低下的人群不断增加， 个体治疗真菌感染是非常困难的，因为真菌与 而且很少有药物能杀死这种真菌而不对宿主产生毒性。与 随着耐药性的出现，新疗法的开发现在至关重要。到 解决这一未满足的医疗需求并确定药物开发的新目标， 这对揭示这些病原体导致人类疾病的机制至关重要。 我发明了一种强大的方法来研究人类防御的前线 对抗这些真菌病原体。宿主先天免疫细胞识别并吞噬 这些真菌细胞能够抵抗入侵的病原体，但真菌细胞能够适应并触发免疫细胞死亡。 我最近发现，这种免疫细胞死亡需要真菌细胞壁重塑， NLRP 3炎性小体。然而，所涉及的具体触发因素和机制 仍然是个谜在这里，我提出了一个跨学科的方法来检查机制 真菌能够诱导宿主细胞死亡的途径，以及 对入侵的病原体做出反应。我们对真菌基因的全球分析 表达、基因功能和宿主免疫反应将提供高分辨率的 描绘了这种宿主-病原体界面，并揭示了治疗方法的新靶点， 人命