Novel mechanisms of Alveolar Macrophage-Dependent Antifungal Innate Immunity
肺泡巨噬细胞依赖性抗真菌先天免疫的新机制
基本信息
- 批准号:10536600
- 负责人:
- 金额:$ 54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-08 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAddressAdrenal Cortex HormonesAlveolar MacrophagesAntibiotic TherapyAntifungal AgentsAreaBasic ScienceCD4 Positive T LymphocytesCandidate Disease GeneCellsCharacteristicsChitinaseChromosome MappingDataDiseaseEventFVB MouseFailureGeneticGoalsGrowthHost DefenseImmunityImmunocompetentImmunocompromised HostImpairmentIn VitroInbred Strains MiceInbreedingInfectionInflammatoryIngestionInjuryInterferon Type IIKnowledgeLaboratoriesLifeLungMacrophageMapsMediatingMissionModelingMouse StrainsMusMycosesNatural ImmunityOrganismOutcomePatient CarePattern recognition receptorPhagocytesPhagocytosisPhagosomesPhenotypePneumocystisPneumocystis InfectionsPneumocystis carinii PneumoniaPredispositionProductionProductivityProteinsQuantitative Trait LociReagentReceptor Protein-Tyrosine KinasesRegulationResearchResearch DesignResistanceResistance to infectionRoleSentinelSurfaceT-LymphocyteTestingTherapeuticTimeUnited States National Institutes of HealthWorkadaptive immunitycandidate identificationdrug discoverygenomic locusimprovedin vivoinhibitorinsightmortalitymouse modelnew therapeutic targetnovelnovel therapeutic interventionpathogenpathogenic fungusprogramsprotein expressionrational designreceptorresistance generespiratorytooltranslational studytransmission processtreatment strategy
项目摘要
Pneumocystis pneumonia (PcP) remains a serious life-threatening respiratory fungal infection of
immunocompromised patients, and one of the most common AIDS-defining illnesses in the US and the
world. PcP-related mortality rates have changed little over the past two decades, likely due to our inability to
adequately treat the infection without exacerbating immunopathogenesis. Adjunctive corticosteroids are used to
suppress inflammatory injury during antibiotic treatment, but the benefit of these broadly acting agents is
uncertain. The mechanisms by which Pc is recognized and cleared from the lung remain incompletely
understood. Alveolar macrophages (AMs) are at the frontline of the host-pathogen interaction, and serve as
important effectors of pulmonary host defense against Pneumocystis. Macrophages possess an array of PRR
that have the potential to recognize Pc, but they are typically ineffective for host defense when CD4+ T cell help
is not available. The reason for this is unknown, but it has been suggested that Pc may actively avoid or suppress
macrophage mediated host defense to insure survival and transmission. Our laboratory has identified an inbred
mouse strain which is unique in its ability to resist Pc infection in the absence of T cells. The resistance phenotype
requires the presence of AMs, and can be overridden by reprogramming the resistant AMs to a susceptible M1
biased phenotype. The identification of resistant and susceptible macrophage phenotypes will provide an
opportunity to explore the divergent host-pathogen interactions associated with either protection or infection. The
overarching hypothesis of this proposal is that differential macrophage polarization, phagocytic processing of Pc,
and antifungal effector production dictates the outcome of the Pc-AM interaction. To test this hypothesis we will
utilize the resistant and susceptible mouse models described in our Preliminary Studies. The identification of
new therapeutic strategies for the treatment of fungal diseases is an active area of drug-discovery research. Our
long-term goal is to understand the mechanisms regulating macrophage mediated innate immunity in the lung
to facilitate the rational design of therapeutic strategies to enhance host defense while limiting
immunopathogenesis. To accomplish this goal we propose Specific Aims that will: 1) define functional differences
in the phagocytic machinery of resistant and susceptible AMs that dictate the outcome of infection; 2) explore
novel antifungal functions for chitinase-like proteins (Chi3l3) and TAM receptors (MerTK); and 3) map the Pc
resistance locus and identify resistance-associated effector molecules that contribute to protective antifungal
innate immunity. Our Preliminary Studies demonstrate that AMs can be programmed for innate protection against
this opportunistic fungal pathogen, and suggest that modifying macrophage function may represent a viable
strategy to enhance antifungal host defense.
肺孢子虫肺炎(PcP)仍然是一种严重的危及生命的呼吸道真菌感染,
免疫功能低下的患者,和一个最常见的艾滋病定义的疾病在美国和
世界在过去的二十年里,与PCP相关的死亡率几乎没有变化,这可能是由于我们无法
充分治疗感染而不加重免疫发病机制。辅助皮质类固醇用于
抑制抗生素治疗期间的炎症损伤,但这些广泛作用的药物的益处是
不确定Pc被识别和从肺中清除的机制仍然不完全
明白肺泡巨噬细胞(AM)处于宿主-病原体相互作用的前线,
肺宿主防御肺孢子虫的重要效应物。宏程序拥有PRR数组
具有识别Pc的潜力,但当CD 4 + T细胞帮助宿主防御时,
不可用.其原因尚不清楚,但有人认为Pc可能会主动回避或抑制
巨噬细胞介导的宿主防御以确保存活和传播。我们的实验室发现了一种近亲繁殖的
小鼠品系,其在缺乏T细胞的情况下具有抵抗Pc感染的能力。耐药表型
需要AM的存在,并且可以通过将抗性AM重新编程为易感M1来覆盖
偏向表型鉴定抗性和敏感性巨噬细胞表型将提供
有机会探索与保护或感染相关的不同宿主-病原体相互作用。的
该提议的主要假设是不同的巨噬细胞极化,Pc的吞噬加工,
并且抗真菌效应物的产生决定了Pc-AM相互作用的结果。为了验证这个假设,我们将
利用我们的初步研究中描述的抗性和易感小鼠模型。的识别
用于治疗真菌疾病的新治疗策略是药物发现研究的活跃领域。我们
长期目标是了解调节肺中巨噬细胞介导的先天免疫的机制
促进治疗策略的合理设计,以增强宿主防御,同时限制
免疫发病机制为了实现这一目标,我们提出了具体的目标,将:1)定义功能差异
在决定感染结果的抗性和易感AM的吞噬机制中; 2)探索
几丁质酶样蛋白(Chi 3l 3)和TAM受体(MerTK)的新的抗真菌功能;和3)绘制Pc
耐药基因座,并确定耐药相关的效应分子,有助于保护性抗真菌
先天免疫我们的初步研究表明,AM可以被编程为先天性保护,
这种机会性真菌病原体,并建议修改巨噬细胞功能可能代表了一个可行的,
增强抗真菌宿主防御的策略。
项目成果
期刊论文数量(0)
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Terry W Wright其他文献
Terry W Wright的其他文献
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{{ truncateString('Terry W Wright', 18)}}的其他基金
Novel mechanisms of Alveolar Macrophage-Dependent Antifungal Innate Immunity
肺泡巨噬细胞依赖性抗真菌先天免疫的新机制
- 批准号:
10311998 - 财政年份:2020
- 资助金额:
$ 54万 - 项目类别:
Novel mechanisms of Alveolar Macrophage-Dependent Antifungal Innate Immunity
肺泡巨噬细胞依赖性抗真菌先天免疫的新机制
- 批准号:
10083184 - 财政年份:2020
- 资助金额:
$ 54万 - 项目类别:
Reversing inhibitory receptor signaling for PcP Therapy
逆转 PcP 疗法的抑制性受体信号传导
- 批准号:
9243968 - 财政年份:2016
- 资助金额:
$ 54万 - 项目类别:
Reversing inhibitory receptor signaling for PcP Therapy
逆转 PcP 疗法的抑制性受体信号传导
- 批准号:
9062825 - 财政年份:2016
- 资助金额:
$ 54万 - 项目类别:
Targeting Inhibitory T cell Receptors for PcP Therapy
靶向抑制性 T 细胞受体进行 PcP 治疗
- 批准号:
8927877 - 财政年份:2015
- 资助金额:
$ 54万 - 项目类别:
Macrophage effector functions during respiratory fungal infection
呼吸道真菌感染期间巨噬细胞效应功能
- 批准号:
8273610 - 财政年份:2012
- 资助金额:
$ 54万 - 项目类别:
Macrophage effector functions during respiratory fungal infection
呼吸道真菌感染期间巨噬细胞效应功能
- 批准号:
8463611 - 财政年份:2012
- 资助金额:
$ 54万 - 项目类别:
Macrophage effector functions during respiratory fungal infection
呼吸道真菌感染期间巨噬细胞效应功能
- 批准号:
8837679 - 财政年份:2012
- 资助金额:
$ 54万 - 项目类别:
Macrophage effector functions during respiratory fungal infection
呼吸道真菌感染期间巨噬细胞效应功能
- 批准号:
8656803 - 财政年份:2012
- 资助金额:
$ 54万 - 项目类别:
Chemokine regulation of immune cell recruitment during Pneumocystis pneumonia
肺孢子虫肺炎期间免疫细胞募集的趋化因子调节
- 批准号:
7207945 - 财政年份:2006
- 资助金额:
$ 54万 - 项目类别:
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