IMMUNE REGULATION AND VACCINE DEVELOPMENT IN LEISHMANIASIS
利什曼病的免疫调节和疫苗开发
基本信息
- 批准号:9563834
- 负责人:
- 金额:$ 52.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AdultBone MarrowC57BL/6 MouseCellsCharacteristicsChronicClinical ResearchColorCuesCutaneousCutaneous LeishmaniasisDendritic CellsDermalDevelopmentDiseaseEmbryoEnvironmentFc ReceptorFlow CytometryGeneticGoalsGrowthHumanImmuneImmunologicsIn VitroIndiaInfectionInflammatoryInterferonsInterleukin-10Interleukin-4LeadLeishmania majorLeishmaniasisLesionMacrophage Colony-Stimulating Factor ReceptorMediator of activation proteinMolecularMononuclearMusNOS2A geneParasitesPhenotypePlayPopulationPreventive vaccinePrimary InfectionProductionRecruitment ActivityResistanceRoleSeveritiesSiteSkinVaccinesVisceral Leishmaniasiscytokinedesignexperimental studyhealingimmunoregulationin vivokillingsmacrophagemannose receptormonocyteneutrophilpathogenpermissivenessradioresistantred fluorescent proteinresponseskin disordertherapeutic vaccinevaccine development
项目摘要
Inflammatory monocytes can be manipulated by environmental cues to perform multiple functions. To define the role of monocytes at primary or secondary sites of infection with an intra-phagosomal pathogen we employed Leishmania major-red fluorescent protein (RFP) parasites and multi-color flow cytometry to define and enumerate infected and uninfected inflammatory cells in the skin. During primary infection, infected monocytes had altered maturation and were the initial mononuclear host cell for parasite replication. At secondary sites, this same population rapidly produced inducible nitric oxide synthase (iNOS) in an IFN- dependent manner and was critical for parasite killing. Maturation to a dendritic cell-like phenotype was not required for monocyte iNOS-production, and enhanced monocyte recruitment correlated with IFN- dependent cxcl10 expression. In contrast, neutrophils were a safe haven for parasite in both primary and secondary sites. Thus, inflammatory monocytes play divergent roles during intra-phagosomal infection at primary versus secondary sites of infection.
The origin and function of dermal macrophages in cutaneous infections remain poorly studied. We found that a strain of Leishmania major (LmSd) that produces non-healing cutaneous lesions in conventionally resistant C57BL/6 mice was more efficiently taken up by M2-polarized bone marrow derived macrophages (BMDMs) in vitro and by mannose receptor (MR)hi dermal macrophages in vivo compared with a healing strain (LmFn). Both in steady and inflammatory states, the MRhi dermal macrophages showed M2 characteristics. Notably, the favored infection of M2 BMDMs by LmSd depends on MR. Both genetic deletion of MR and selective depletion of MRhi dermal macrophages by anti-CSF-1 receptor antibody reversed the non-healing phenotype. The MRhi dermal macrophages were radio-resistant and not replaced by adult bone marrow-derived cells during infection, but were locally maintained by IL-4 and IL-10. We conclude that embryonic-derived, M2-like dermal macrophages are permissive for parasite growth even in a strong TH1 immune environment, and the preferential infection of these cells plays a crucial role in the severity of cutaneous disease.
炎性单核细胞可以通过环境线索来操纵以执行多种功能。为了确定单核细胞在吞噬体内病原体感染的原发或继发部位的作用,我们采用利什曼原虫主要红色荧光蛋白(RFP)寄生虫和多色流式细胞术来定义和计数皮肤中感染和未感染的炎性细胞。在初次感染过程中,受感染的单核细胞成熟改变,是寄生虫复制的初始单核宿主细胞。在第二个位点,同样的人群以IFN依赖的方式迅速产生诱导型一氧化氮合酶(iNOS),这对杀死寄生虫至关重要。单核细胞iNOS的产生不需要成熟为树突状细胞样表型,并且增强的单核细胞募集与IFN依赖性cxcl 10表达相关。相比之下,中性粒细胞是寄生虫在原发和继发部位的避风港。因此,炎症性单核细胞在吞噬体内感染期间在原发感染部位与继发感染部位发挥不同的作用。
真皮巨噬细胞在皮肤感染中的起源和功能研究仍然很少。我们发现,在传统耐药C57 BL/6小鼠中产生不可愈合皮肤病变的大型利什曼原虫菌株(LmSd)在体外被M2极化骨髓源性巨噬细胞(BMDM)和体内被甘露糖受体(MR)更有效地吸收与治愈菌株(LmFn)相比。在稳态和炎症状态下,MRhi真皮巨噬细胞均显示M2特征。值得注意的是,LmSd对M2 BMDM的有利感染取决于MR。MR的基因缺失和抗CSF-1受体抗体对MR真皮巨噬细胞的选择性消耗都逆转了非愈合表型。MRhi真皮巨噬细胞具有放射抗性,并且在感染期间不被成人骨髓来源的细胞取代,而是由IL-4和IL-10局部维持。我们的结论是,胚胎来源的,M2样真皮巨噬细胞是允许寄生虫生长,即使在一个强大的TH 1免疫环境,这些细胞的优先感染起着至关重要的作用,皮肤疾病的严重程度。
项目成果
期刊论文数量(0)
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David Sacks其他文献
David Sacks的其他文献
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{{ truncateString('David Sacks', 18)}}的其他基金
ANALYSIS OF T CELL RESPONSES IN HUMAN LEISHMANIASIS
人类利什曼病 T 细胞反应分析
- 批准号:
6431576 - 财政年份:
- 资助金额:
$ 52.93万 - 项目类别:
Developmental Biology Of Leishmania Promastigotes
利什曼原虫前鞭毛体的发育生物学
- 批准号:
6668897 - 财政年份:
- 资助金额:
$ 52.93万 - 项目类别:
IMMUNE REGULATION AND VACCINE DEVELOPMENT IN LEISHMANIASIS
利什曼病的免疫调节和疫苗开发
- 批准号:
8745304 - 财政年份:
- 资助金额:
$ 52.93万 - 项目类别:
IMMUNE REGULATION AND VACCINE DEVELOPMENT IN LEISHMANIASIS
利什曼病的免疫调节和疫苗开发
- 批准号:
7732462 - 财政年份:
- 资助金额:
$ 52.93万 - 项目类别:
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