Cellular and molecular mechanisms involving SLAMF1 during pulmonary fungal infection
肺部真菌感染过程中涉及SLAMF1的细胞和分子机制
基本信息
- 批准号:10738468
- 负责人:
- 金额:$ 19.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-19 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AbbreviationsAddressAlveolarAntibodiesBlastomyces dermatitidisBone MarrowCD4 Positive T LymphocytesCause of DeathCellsColony-forming unitsDataDefectDendritic CellsDevelopmentEffector CellEndowmentEpithelial CellsExclusionFamilyFutureGrowthHematopoieticHourImmuneIn VitroInfectionInnate Immune ResponseKnowledgeLeukocytesLungLung infectionsLymphocyteLymphoid CellMediatingMedicalMicrobeModelingMolecularMucous MembraneMusMycosesMyeloid CellsNatural ImmunityNatural Killer CellsNeutrophil ActivationNitric OxidePathway interactionsPhagocytesPharmaceutical PreparationsPopulationProductionPublishingReactive Oxygen SpeciesReceptor SignalingReportingResistanceRoleSignal TransductionStainsStromal CellsT-LymphocyteTestingTherapeuticUnited StatesVaccinesWild Type MouseWorkYeastsantimicrobialcombatdesignfungusin vivoinnovationinsightmicrobialmonocytemouse modelneutrophilnovelnovel therapeutic interventionpathogenpathogenic funguspathogenic microbereceptorrespiratoryrestraintsensortherapeutically effectivevaccine development
项目摘要
PROJECT SUMMARY/ABSTRACT
Lung cellular resistance against microbes requires a signaling network involving stroma and innate myeloid
and lymphoid cells. To date, the signaling receptors and pathways are incompletely understood. Signaling
Lymphocyte Molecule Family (SLAMF) receptors are widely expressed among hematopoietic cells and lung
epithelial cells making them ideal candidates to orchestrate phagocyte killing of microbes. We recently reported
that during pulmonary infection with the fungus Blastomyces dermatitidis (Bd), SLAMF1 is required for innate
immunity and dispensable for priming vaccine-induced CD4+ Tcells. In preliminary data, we found that
SLAMF1 is required for killing of the yeast by neutrophils and monocytes in vivo, but the receptor is dispensible
for killing in vitro. These findings suggest that extrinsic, SLAMF1 dependent signals activate phagocytes to kill
yeast in vivo.
In this application, we propose to elucidate where and how SLAMF1 receptors endow phagocytes with the
ability to kill yeast in vivo during pulmonary fungal infection. We hypothesize that innate lymphocytes and
CCR2+ monocytes are required for SLAMF1-mediated neutrophil activation. We also posit that SLAMF1
mediates its function through homophilic (SLAMF1:SLAMF1) interactions between innate lymphocytes
and monocytes or through direct sensing of the yeast by SLAMF1. We provide strong preliminary data to
support our hypotheses. By using a panel of antibodies directed against 17 pulmonary leukocyte populations,
we found SLAMF1 staining on CD4+TCR+, TCR+, MAIT cells and Ly6Chi CCR2+ monocytes at 16 hours
post-infection. Our workplan in Aim 1 offers approaches that will elucidate the requirement of SLAMF1 on
lymphoid, myeloid or stromal cells for activation of neutrophil killing of yeast. In Aim 2, we will define the mode
of SLAMF1 action by distinguishing between SLAMF1 homophilic interactions among cells that express the
receptor vs. direct sensing of yeast by SLAMF1. Our work will identify new mechanisms of receptor-mediated
activation of innate effector cells and lay the groundwork for subsequent studies to advance detailed
mechanistic insight into how SLAMF1 orchestrates signaling and activation of neutrophils, as these cells are
the most potent effector to combat fungal and other microbial pathogens. This knowledge will provide the basis
for developing and designing new strategies for therapeutic treatments against fungi, and other pathogenic
microbes that require innate immunity for pathogen restraint.
项目总结/文摘
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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Marcel Wuethrich其他文献
Marcel Wuethrich的其他文献
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{{ truncateString('Marcel Wuethrich', 18)}}的其他基金
Regulation of vaccine-induced anti-fungal T17 cells
疫苗诱导的抗真菌 T17 细胞的调节
- 批准号:
8194616 - 财政年份:2011
- 资助金额:
$ 19.44万 - 项目类别:
Regulation of vaccine-induced anti-fungal T17 cells
疫苗诱导的抗真菌 T17 细胞的调节
- 批准号:
8450924 - 财政年份:2011
- 资助金额:
$ 19.44万 - 项目类别:
Regulation of vaccine-induced anti-fungal Th17 cells
疫苗诱导的抗真菌 Th17 细胞的调节
- 批准号:
9381740 - 财政年份:2011
- 资助金额:
$ 19.44万 - 项目类别:
Regulation of vaccine-induced anti-fungal T17 cells
疫苗诱导的抗真菌 T17 细胞的调节
- 批准号:
8262154 - 财政年份:2011
- 资助金额:
$ 19.44万 - 项目类别:
Regulation of vaccine-induced anti-fungal T17 cells
疫苗诱导的抗真菌 T17 细胞的调节
- 批准号:
8836476 - 财政年份:2011
- 资助金额:
$ 19.44万 - 项目类别:
Regulation of vaccine-induced anti-fungal Th17 cells
疫苗诱导的抗真菌 Th17 细胞的调节
- 批准号:
9976397 - 财政年份:2011
- 资助金额:
$ 19.44万 - 项目类别:
Regulation of vaccine-induced anti-fungal T17 cells
疫苗诱导的抗真菌 T17 细胞的调节
- 批准号:
8651410 - 财政年份:2011
- 资助金额:
$ 19.44万 - 项目类别:
Priming of Antifungal T-Cells at Mucosal and Systemic Sites
粘膜和全身部位抗真菌 T 细胞的启动
- 批准号:
7540447 - 财政年份:2007
- 资助金额:
$ 19.44万 - 项目类别:
Priming of Antifungal T-Cells at Mucosal and Systemic Sites
粘膜和全身部位抗真菌 T 细胞的启动
- 批准号:
7359255 - 财政年份:2007
- 资助金额:
$ 19.44万 - 项目类别:
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