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Antifungal Immunity and the Mechanism of Fungal Programmed Cell Death

抗真菌免疫和真菌程序性细胞死亡机制

基本信息

批准号：
10538624
负责人：
Robert Andrew Cramer
金额：
$ 65.3万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-22 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10538624
关键词：
Antifungal Agents Apoptosis Apoptosis Inhibitor Apoptosis Regulation Gene Apoptotic Applications Grants Aspergillosis Aspergillus fumigatus Aspergillus nidulans Baculoviruses Biochemical Biochemistry Biological Models Candida albicans Candidiasis Cartoons Caspase Cell Death Cell Death Induction Cells Collaborations Complement DNA Fragmentation Data Defect Development Disease Disease Outcome Enzymes Essential Genes Etiology Eukaryota Family Fungal Genes Fungal Proteins Fungal Spores Genetic Genetic study Germination Goals Histones Homologous Gene Host Defense Human Hyphae Immune Immunity Immunologic Surveillance Immunologics Immunology Induction of Apoptosis Inhalation Innate Immune System Knowledge Laboratories Lung Mediating Modeling Molds Myelogenous NADPH Oxidase Oxidative Stress Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Phagocytes Pharmacology Study Physiology Play Pneumonia Post-Translational Regulation Predisposition Process Proteins Regulation Reporter Reporting Reproduction spores Research Personnel Resistance Respiratory Burst Role Stress System Tertiary Protein Structure Testing Therapeutic Tissues Virulence Visualization Work experience fungal genetics immune checkpoint immune function improved in vivo innovation insight member new therapeutic target novel novel therapeutic intervention pathogenic fungus pharmacologic predictive modeling prevent respiratory response

项目摘要

PROJECT SUMMARY Humans inhale fungal conidia (i.e, vegetative spores) on a daily basis. The ability of the respiratory innate immune system to prevent germination of inhaled conidia into tissue-invasive hyphae represents a critical immunologic checkpoint. Using Aspergillus fumigatus, the most common etiologic agent of invasive aspergillosis, as a model system for human fungal pathogens, we discovered that conidia undergo programmed cell death with apoptosis-like features during interactions with innate immune cells. This finding was facilitated by a novel fluorescent reporter of fungal physiology that enables visualization and quantitation of fungal apoptosis markers, including histone degradation, caspase activation, and DNA fragmentation. Our work demonstrates that A. fumigatus conidia express an essential and druggable anti-apoptotic protein, termed Bir1, that counters host induction of apoptosis-like programmed cell death by the action of phagocyte NADPH oxidase. Genetic and pharmacologic studies demonstrate that Bir1 expression and activity underlie conidial susceptibility to host apoptosis-like programmed cell death, and in turn, host susceptibility to invasive aspergillosis. These findings indicate that mammalian fungal immune surveillance exploits a fungal apoptosis- like programmed cell death pathway to maintain barrier immunity in the lung. In this collaborative proposal with two co-investigators, we seek to determine the mechanism through which Bir1 regulates anti-apoptotic activity during fungal-host cell encounters. Our preliminary data support a model in which Bir1 exerts anti-apoptotic activity via two conserved BIR domains, underlies post-translational regulation in response to pro-apoptotic stress, regulates candidate fungal caspase-like enzymes as apoptosis effectors, and demonstrates functional conservation across human pathogenic fungi. Based on these observations, our model predicts that fungal apoptosis-like programmed cell death is a general feature of fungal-host cell encounters and central to the establishment of invasive fungal disease. We explore this model in the following aims: (1) define the functional domains and post-translational regulation of Bir1 critical for resistance to host induction of apoptosis-like programmed cell death, (2) define the mechanism of Bir1- mediated resistance to host induction of apoptosis-like programmed cell death, with an emphasis on regulation of a candidate fungal caspase-like activity, and (3) define the role of apoptosis-like programmed cell death and Bir1 homologs following Aspergillus nidulans and Candida albicans challenge. The proposed studies are significant and innovative because they identify a novel mechanism of immune surveillance and demonstrate that higher eukaryotes can exploit programmed cell death in lower eukaryotes for the purpose of sterilizing immunity. This work will provide a mechanistic understanding of Bir1 function in regulating host-fungal encounters. Knowledge gained from these studies will inform strategies that target fungal Bir1 homologs and exploit fungal apoptosis-like programmed cell death for therapeutic gain.

项目总结人类每天都会吸入真菌分生孢子(即营养孢子)。呼吸先天的能力免疫系统防止吸入的分生孢子萌发成组织侵袭的菌丝代表着一个关键免疫检查站。使用最常见的侵袭性病原体烟曲霉菌曲霉病，作为人类真菌病原体的模型系统，我们发现分生孢子经历了在与先天免疫细胞相互作用过程中，具有类凋亡特征的程序性细胞死亡。这一发现是由一种新型的真菌生理学荧光报告器促进的，它能够进行可视化和定量真菌凋亡标记物，包括组蛋白降解、半胱氨酸氨基转移酶激活和DNA片段化。我们的工作表明，烟曲霉分生孢子表达一种必要的和可药物的抗凋亡蛋白，名为BI1，通过吞噬细胞的作用对抗宿主诱导的类凋亡细胞程序性死亡 NADPH氧化酶。遗传学和药理学研究表明，Bir1的表达和活性是分生孢子对宿主类细胞凋亡的敏感性，进而宿主对侵袭性的敏感性曲霉病。这些发现表明，哺乳动物的真菌免疫监测利用了真菌细胞凋亡- 如程序化的细胞死亡途径，以维持肺内的屏障免疫。在这项与两名共同调查人员合作的提案中，我们试图确定通过什么机制在真菌-宿主细胞接触过程中，BIR1调节抗凋亡活性。我们的初步数据支持一个模型其中Bir1通过两个保守的BIR结构域发挥抗凋亡活性，是翻译后的基础对促凋亡应激的调节，将候选真菌caspase样酶调节为细胞凋亡效应器，并展示了在人类致病真菌中的功能保守。基于这些观察发现，我们的模型预测，真菌类凋亡的程序性细胞死亡是真菌-宿主细胞相遇，并在侵袭性真菌疾病的建立中处于中心地位。我们探索了这一模式在以下目标中：(1)定义BIR1的功能结构域和翻译后调控抵抗宿主诱导的类凋亡程序性细胞死亡，(2)定义了Bir1- 介导对宿主诱导的类凋亡程序性细胞死亡的抵抗，并强调调节和(3)定义了凋亡样细胞程序性死亡和 Nidulans曲霉和白色念珠菌挑战后的Bir1同源物。建议进行的研究包括具有重大意义和创新性，因为它们确定了一种新的免疫监视机制，并证明了高等真核生物可以利用低等真核生物的程序性细胞死亡来进行绝育豁免权。这项工作将提供对Bir1在调节寄主真菌中的功能的机制的理解相遇。从这些研究中获得的知识将成为针对真菌BI1同源物和利用类似真菌凋亡的程序性细胞死亡来获得治疗收益。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Customization of a DADA2-based pipeline for fungal internal transcribed spacer 1 (ITS1) amplicon data sets.

DOI：
10.1172/jci.insight.151663
发表时间：
2022-01-11
期刊：
JCI insight
影响因子：
8
作者：
Rolling T;Zhai B;Frame J;Hohl TM;Taur Y
通讯作者：
Taur Y

Menacing Mold: Recent Advances in Aspergillus Pathogenesis and Host Defense.

DOI：
10.1016/j.jmb.2019.03.027
发表时间：
2019-10
期刊：
Journal of molecular biology
影响因子：
5.6
作者：
Benjamin Y Tischler;T. Hohl
通讯作者：
Benjamin Y Tischler;T. Hohl

Call to Action: How to Tackle Emerging Nosocomial Fungal Infections.

DOI：
10.1016/j.chom.2020.04.011
发表时间：
2020-06-10
期刊：
Cell host & microbe
影响因子：
30.3
作者：
Lionakis MS;Hohl TM
通讯作者：
Hohl TM

Minority report: the intestinal mycobiota in systemic infections.

少数族裔报告：全身感染中的肠道菌菌群。

DOI：
10.1016/j.mib.2020.05.004
发表时间：
2020-08
期刊：
Current opinion in microbiology
影响因子：
5.4
作者：
Rolling T;Hohl TM;Zhai B
通讯作者：
Zhai B

Immunity to fungi in the lung.

DOI：
10.1016/j.smim.2023.101728
发表时间：
2023-03
期刊：
SEMINARS IN IMMUNOLOGY
影响因子：
7.8
作者：
Heung, Lena J.;Wiesner, Darin L.;Wang, Keyi;Rivera, Amariliz;Hohl, Tobias M.
通讯作者：
Hohl, Tobias M.