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:
- 金额:$ 65.3万
- 依托单位:
- 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:
- 关键词:Antifungal AgentsApoptosisApoptosis InhibitorApoptosis Regulation GeneApoptoticApplications GrantsAspergillosisAspergillus fumigatusAspergillus nidulansBaculovirusesBiochemicalBiochemistryBiological ModelsCandida albicansCandidiasisCartoonsCaspaseCell DeathCell Death InductionCellsCollaborationsComplementDNA FragmentationDataDefectDevelopmentDiseaseDisease OutcomeEnzymesEssential GenesEtiologyEukaryotaFamilyFungal GenesFungal ProteinsFungal SporesGeneticGenetic studyGerminationGoalsHistonesHomologous GeneHost DefenseHumanHyphaeImmuneImmunityImmunologic SurveillanceImmunologicsImmunologyInduction of ApoptosisInhalationInnate Immune SystemKnowledgeLaboratoriesLungMediatingModelingMoldsMyelogenousNADPH OxidaseOxidative StressPathogenesisPathway interactionsPatient-Focused OutcomesPatientsPhagocytesPharmacology StudyPhysiologyPlayPneumoniaPost-Translational RegulationPredispositionProcessProteinsRegulationReporterReportingReproduction sporesResearch PersonnelResistanceRespiratory BurstRoleStressSystemTertiary Protein StructureTestingTherapeuticTissuesVirulenceVisualizationWorkexperiencefungal geneticsimmune checkpointimmune functionimprovedin vivoinnovationinsightmembernew therapeutic targetnovelnovel therapeutic interventionpathogenic funguspharmacologicpredictive modelingpreventrespiratoryresponse
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.
项目摘要
人类每天都会吸入真菌分生孢子(即营养孢子)。先天呼吸能力
免疫系统阻止吸入分生孢子萌发成组织侵入性菌丝是一个关键
免疫检查点使用烟曲霉,最常见的病原体的侵袭性
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
在与先天免疫细胞的相互作用期间,具有类凋亡特征的程序性细胞死亡。这一发现
通过一种新的荧光真菌生理学报告,
真菌凋亡标志物,包括组蛋白降解,半胱天冬酶激活,和DNA片段。
我们的工作表明,A.烟曲霉分生孢子表达必需且可药用的抗凋亡蛋白,
称为Bir 1,其对抗宿主通过吞噬细胞的作用诱导的类凋亡的程序性细胞死亡
NADPH氧化酶。遗传和药理学研究表明,Bir 1的表达和活性是
分生孢子对寄主寄生虫样程序性细胞死亡的敏感性,反过来,寄主对入侵性
曲霉病这些发现表明,哺乳动物真菌免疫监视利用真菌细胞凋亡-
比如通过程序性细胞死亡途径来维持肺部的屏障免疫。
在这项与两名共同调查员的合作提案中,我们试图确定一种机制,
Bir 1在真菌-宿主细胞相遇期间调节抗凋亡活性。我们的初步数据支持一个模型
其中Bir 1通过两个保守的BIR结构域发挥抗凋亡活性,
调节响应于促凋亡应激,调节候选真菌半胱天冬酶样酶作为细胞凋亡
效应子,并在人类致病真菌中表现出功能保守性。基于这些
观察,我们的模型预测,真菌性骨化样程序性细胞死亡是一个普遍的特点,
真菌-宿主细胞相遇,并对侵袭性真菌疾病的建立起重要作用。我们探索这个模型
(1)确定Bir 1的功能结构域和翻译后调控,
对宿主诱导的类凋亡样程序性细胞死亡的抗性,(2)确定Bir 1-
介导的对宿主诱导的类凋亡的程序性细胞死亡的抗性,重点是调节
的候选真菌半胱天冬酶样活性,和(3)定义类凋亡的程序性细胞死亡的作用,
构巢曲霉和白色念珠菌挑战后的Bir 1同源物。拟议的研究是
因为它们确定了一种新免疫监视机制,
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达到消毒的目的,
免疫力这项工作将提供一个机制的理解Bir 1的功能,在调节宿主真菌
遭遇从这些研究中获得的知识将为靶向真菌Bir 1同源物的策略提供信息,
利用真菌性类骨化症的程序性细胞死亡来获得治疗效果。
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:
- 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:
- 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:
- 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:
- 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:
- 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.
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Robert Andrew Cramer其他文献
Robert Andrew Cramer的其他文献
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{{ truncateString('Robert Andrew Cramer', 18)}}的其他基金
Environmental Oxygen Transitions and Aspergillosis Disease Progression
环境氧转变和曲霉病进展
- 批准号:
10615129 - 财政年份:2019
- 资助金额:
$ 65.3万 - 项目类别:
Environmental Oxygen Transitions and Aspergillosis Disease Progression
环境氧转变和曲霉病进展
- 批准号:
10404535 - 财政年份:2019
- 资助金额:
$ 65.3万 - 项目类别:
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
- 批准号:
10320401 - 财政年份:2019
- 资助金额:
$ 65.3万 - 项目类别:
Overcoming Emerging Aspergillus fumigatus Azole Resistance Via Protease Inhibition
通过蛋白酶抑制克服新出现的烟曲霉唑抗性
- 批准号:
10547781 - 财政年份:2019
- 资助金额:
$ 65.3万 - 项目类别:
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
- 批准号:
10079460 - 财政年份:2019
- 资助金额:
$ 65.3万 - 项目类别:
Environmental Oxygen Transitions and Aspergillosis Disease Progression
环境氧转变和曲霉病进展
- 批准号:
10161719 - 财政年份:2019
- 资助金额:
$ 65.3万 - 项目类别:
Overcoming Emerging Aspergillus fumigatus Azole Resistance Via Protease Inhibition
通过蛋白酶抑制克服新出现的烟曲霉唑抗性
- 批准号:
10320260 - 财政年份:2019
- 资助金额:
$ 65.3万 - 项目类别:
Overcoming Emerging Aspergillus fumigatus Azole Resistance Via Protease Inhibition
通过蛋白酶抑制克服新出现的烟曲霉唑抗性
- 批准号:
10334562 - 财政年份:2019
- 资助金额:
$ 65.3万 - 项目类别:
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