Global analysis of circuitry governing fungal activation of host inflammation

项目摘要/摘要 真菌病原体在全球范围内对人类健康造成毁灭性的损失，真菌 由于免疫功能低下的人口不断增长，感染人数正在上升 个人。治疗真菌感染是极其困难的，因为真菌与 而且很少有药物可以在没有宿主毒性的情况下杀死这种真菌。与 随着耐药性的出现，开发新的治疗方法至关重要。至 解决这一未得到满足的医疗需求并确定药物开发的新目标，这是 对于发现使这些病原体导致人类疾病的机制至关重要。 我开发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 入侵病原体，但真菌细胞能够适应并引发免疫细胞死亡。 我最近发现，这种免疫细胞死亡需要真菌细胞壁重塑和 NLRP3炎症体。然而，涉及的具体触发和机制 仍然是个谜。在这里，我提出了一种跨学科的方法来检查机制 真菌通过这些途径能够诱导宿主细胞死亡，而宿主途径 对入侵的病原体作出反应所必需的。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 描绘了这种宿主-病原体的界面，并揭示了治疗需要挽救的新靶点 人类的生命。

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.