Abstract：
The clearance of the pathogenic fungus, Histoplasma capsulatum, requires cooperation between innate and adaptive immunity. Since this organism is inhaled, lung macrophages and dendritic cells (DCs) are the first lines of defense. Moreover, DCs act as APCs to drive the education of type 1 Th cells to produce IFNγ, which contributes to the final elimination of H. capsulatum. In this study, we explored the importance of Notch signaling in host defenses using a mouse model of pulmonary histoplasmosis. We found up-regulation of Notch ligands (NLs) and Notch receptors (NRs) on phagocytes and IFNγ+ CD4+ T cells upon infection in lungs and lymph nodes. To ascertain the influence of Notch on the course of infection, we used a gamma-secretase inhibitor (GSI), LY-411,575, which inhibits NR downstream signaling. This compound impaired fungal clearance when given at the time of infection or 7 days after infection. However, GSI did not impact fungal clearance in mice with preexisting immunity. The dampened host defenses were associated with reduced differentiation and maturation of monocyte-derived DCs and elevatmonocyte-derived macrophage and alveolar macrophage polarization to M2. Our study reveals the critical nature of Notch signaling in maintaining control of this infectious agent.
摘要：
病原真菌的清除，荚膜组织胞浆，需要先天免疫和适应性免疫之间的合作。由于这种生物被吸入，肺巨噬细胞和树突状细胞（DC）是第一道防线。此外，DC作为APC驱动1型Th细胞产生IFNγ的教育，这有助于最终消除荚膜H.在这项研究中,我们使用肺组织胞浆菌病小鼠模型探讨了Notch信号在宿主防御中的重要性.我们发现在肺部和淋巴结感染后，吞噬细胞和IFNγCD4T细胞上的Notch配体（NL）和Notch受体（NRs）上调。为了确定Notch对感染过程的影响，我们使用了γ-分泌酶抑制剂(GSI),LY-411,575,其抑制NR下游信号传导。当在感染时或感染后7天给予时,该化合物损害真菌清除。然而,GSI不影响具有预先存在的免疫力的小鼠的真菌清除。宿主防御减弱与单核细胞衍生的DC和单核细胞衍生的巨噬细胞和肺泡巨噬细胞向M2的分化和成熟降低有关。我们的研究揭示了Notch信号在维持这种感染因子控制方面的关键性质。
