IMMUNE REGULATION AND VACCINE DEVELOPMENT IN LEISHMANIASIS

炎症单核细胞可以被环境因素操纵来执行多种功能。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，我们使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枚举皮肤中感染和未感染的炎症细胞。在初次感染期间，受感染的单核细胞成熟改变，成为寄生虫复制的初始单核宿主细胞。在次要位点，同一种群以依赖IFN的方式快速产生诱导型一氧化氮合酶（iNOS），对寄生虫的杀死至关重要。单核细胞inos的产生并不需要成熟为树突状细胞样表型，而单核细胞募集的增强与IFN依赖性的cxcl10表达相关。相比之下，中性粒细胞在初级和次级部位都是寄生虫的避风港。因此，炎性单核细胞在吞噬体内感染的原发性和继发性感染中发挥不同的作用。

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.