Lung epithelial cell regulation of immunity to inhaled fungi
肺上皮细胞对吸入真菌免疫的调节
基本信息
- 批准号:9975090
- 负责人:
- 金额:$ 46.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-01 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAirAlveolarAntifungal AgentsBehaviorBlastomycesC Type Lectin ReceptorsCCL20 geneCRISPR/Cas technologyCell LineCell LineageCellsConfocal MicroscopyDataDefense MechanismsEcosystemElementsEnterobacteria phage P1 Cre recombinaseEpithelialEpithelial CellsEpitheliumEventFosteringFungal SporesGenesGranulocyte-Macrophage Colony-Stimulating FactorHematopoieticHistoplasmaHost DefenseHumanImageImmunityIndividualInfectionInflammatoryInhalationInterleukin-1Interleukin-17Interleukin-18Interleukin-6KnowledgeLearningLeukocytesLife StyleLinkLocationLungLung InflammationLymphocyteMammalian CellMolecularMucosal ImmunityMucous MembraneMusMyelogenousMyeloid CellsNatural ImmunityNeurosecretory SystemsOutcomePathogenicityPersonsProductionPublic HealthRegulationReporterReproduction sporesResistanceRespiratory MucosaRoleSignal PathwaySignal TransductionSourceT-LymphocyteTestingTransgenic MiceWorkclimate changecytokinedesignextracellularfungusgenome editingimprovedin vivoinsightinterleukin-22interleukin-23lymphocyte productparticlepathogenpathogenic funguspromoterreceptorrecruitresponserestrainttherapeutic targettissue repairtoolγδ T cells
项目摘要
PROJECT SUMMARY
We propose to define how lung epithelial cells (EC) sense and respond to inhaled fungi. A person inhales a
billion spores/day, but the modes by which fungi are sensed and restrained in lung are unclear. Our preliminary
data reveal that EC regulate mucosal immunity to two primary pathogens, Blastomyces and Histoplasma. We
find that EC NF-κB activation is essential, as are upstream signals of IL-1R, MyD88 and CARD9 and mobiliza-
tion of innate lymphocytes that make IL-17 and GM-CSF. We posit that EC subsets, notably Club cells, sense
fungi and regulate innate immunity, and that EC intrinsic signals via IL-1R and MyD88 drive NFkB-regulated
products to trigger IL-17- and GM-CSF-producing innate lymphocytes, which recruit/activate myeloid effectors.
The lung contains 6 EC subsets: alveolar, club (formerly clara), goblet, neuroendocrine, basal and ciliated
columnar. We'll test the role of Club cells in regulating mucosal immunity by using transgenic mice that display
a lineage-specific GFP reporter to track and analyze the behavior of this subset and, since our reporter mouse
harbors cre recombinase, test its role in resistance by crossing the mouse with IKK2fl/fl or CRISPR/Cas9 mice
to block NF-κB signaling. To learn how EC mobilize innate immunity to fungi, we will use two fungal pathogens
that represent paradigmatic extracellular (Blastomyces) and intracellular (Histoplasma) pathogenic lifestyles
that confront the epithelium of mammalian lungs. Our aims are to:
1. Delineate the role and action of Club cells in sensing inhaled fungi. By using NFκB-eGFP reporter mice,
advanced imaging and FACS analysis, we will track the timing and location of activation of EC and hemato-
poietic cells in response to inhaled fungi. Transgenic mice will be used to dissect the roles of Club cells and
their signaling pathways and downstream products in resistance, and CRISPR/Cas9 used to GFP tag, iso-
late, profile and functionally interrogate specific functions of Club cells in regulating innate immunity.
2. Define how Club cells and products regulate γδ T cells and nTh17 cells to restrain inhaled fungi. We will
define the regulatory role of Club cells and their signals on anti-fungal TCR γδ and nTh17 cells – e.g. activa-
tion or recruitment and cytokine production. The role of innate T cell IL-17A, GM-CSF and IL-22 will be dis-
sected in promoting killing of fungi and fostering EC integrity. Soluble signals such as CCL20, IL-1, IL-6, IL-
18 & IL-23 that activate innate T cells in mice and humans will be defined, and the cell source(s) identified.
Our work will reveal how lung Club cells regulate innate mucosal immunity to fungi offering conceptually new
insight and powerful gene editing tools that will advance the field. By divining antifungal defense mechanisms,
we will improve prospects for therapeutically targeting early events designed to optimize mucosal immunity to
fungi and lung inflammation.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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BRUCE Steven KLEIN其他文献
BRUCE Steven KLEIN的其他文献
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{{ truncateString('BRUCE Steven KLEIN', 18)}}的其他基金
Mechanisms of vaccine immunity against coccidioidomycosis
球孢子菌病疫苗免疫机制
- 批准号:
10584260 - 财政年份:2023
- 资助金额:
$ 46.17万 - 项目类别:
Mechanisms of Vaccine Immunity against Coccidioidomycosis
球孢子菌病疫苗免疫机制
- 批准号:
10591641 - 财政年份:2022
- 资助金额:
$ 46.17万 - 项目类别:
Lung epithelial cell regulation of immunity to inhaled fungi
肺上皮细胞对吸入真菌免疫的调节
- 批准号:
10222492 - 财政年份:2018
- 资助金额:
$ 46.17万 - 项目类别:
Lung epithelial cell regulation of immunity to inhaled fungi
肺上皮细胞对吸入真菌免疫的调节
- 批准号:
10451274 - 财政年份:2018
- 资助金额:
$ 46.17万 - 项目类别:
Combination Adjuvants to Program Durable Immunity to Respiratory Viral and Fungal Pathogens
组合佐剂可对呼吸道病毒和真菌病原体产生持久免疫
- 批准号:
10614603 - 财政年份:2016
- 资助金额:
$ 46.17万 - 项目类别:
Combination Adjuvants to Program Durable Immunity to Respiratory Viral and Fungal Pathogens
组合佐剂可对呼吸道病毒和真菌病原体产生持久免疫
- 批准号:
10224468 - 财政年份:2016
- 资助金额:
$ 46.17万 - 项目类别:
Combination Adjuvants to Program Durable Immunity to Respiratory Viral and Fungal Pathogens
组合佐剂可对呼吸道病毒和真菌病原体产生持久免疫
- 批准号:
10448406 - 财政年份:2016
- 资助金额:
$ 46.17万 - 项目类别:
Combination Adjuvants to Program Durable Immunity to Respiratory Viral and Fungal Pathogens
组合佐剂可对呼吸道病毒和真菌病原体产生持久免疫
- 批准号:
10544356 - 财政年份:2016
- 资助金额:
$ 46.17万 - 项目类别:
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