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:
- 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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