Unraveling Mechanisms of Plasmacytoid Dendritic Cell Priming by CD169+ Macrophages in Severe Murine Malaria

项目摘要 疟疾仍然是全球寄生虫导致死亡的主要原因。仅在2015年，世界卫生组织就报告了约200起 100万例和约50万例因进展至高度炎症性疾病状态而死亡， 疟疾然而，在受感染的宿主中，引发死亡的免疫细胞和炎症因子并不好 明白使用约氏疟原虫（Py）YM作为致死性血液期感染的小鼠模型，我们发现， I型IFN在促进致命疾病中起关键作用。我们发现，在Py YM的急性期， 感染时，浆细胞样树突状细胞（pDC）是系统性I型IFN的主要来源。重要的是， 我们发现，pDC的I型IFN的稳健产生需要CD 169+巨噬细胞的存在 （CD 169 + MP）和用于细胞质DNA传感的衔接分子-STING（干扰素刺激剂 基因）-在MP所属的抗辐射隔室中。此外，我们发现，pDC逮捕和 用活体双光子荧光显微镜观察Py YM感染小鼠骨髓中CD 169 + MP的聚集 显微镜因此，我们假设CD 169 + MP在pDCs表达过程中向pDCs提供接触依赖性信号。 感染，“引发”他们产生大量的I型IFN。我们正在研究 控制MP/pDC相互作用和CD 169 + MP提供的STING依赖性信号的性质， pDC。我们相信这项工作将有助于阐明pDC在严重疟疾中是如何被激活的，这可以作为 在疟疾和潜在的其它I型IFN驱动的疾病中调节I型IFN产生的基础。

Project Summary Malaria remains the leading cause of parasite driven death worldwide. In 2015 alone, the WHO reported ~200 million cases and ~ half a million deaths from progression to the highly inflammatory disease state, severe malaria. Yet the immune cells and inflammatory factors that trigger death in infected hosts are not well understood. Using Plasmodium yoelii (Py) YM as a murine model of lethal blood stage infection, we found that type I IFN plays a key role in promoting fatal disease. We showed that during the acute phase of Py YM infection, plasmacytoid dendritic cells (pDCs) are the predominant source of systemic type I IFN. Importantly, we revealed that robust production of type I IFN by pDCs requires the presence of CD169+ macrophages (CD169+ MP) and the adapter molecule for cytoplasmic DNA sensing—STING (stimulator of interferon genes)—in the radio-resistant compartment to which MP belong. In addition, we found that pDCs arrest and cluster around CD169+ MPs in the bone marrow of Py YM-infected mice using intravital two-photon microscopy. We thus hypothesize that CD169+ MPs provide contact dependent signals to pDCs during infection, “priming” them to produce large quantities of type I IFN. We are investigating the mechanisms that govern MP/pDC interactions and the nature of the STING-dependent signals that CD169+ MPs provide to pDCs. We believe this work will help elucidate how pDCs are activated in severe malaria, which could serve as the basis for tuning of type I IFN production in malaria and potentially other type I IFN driven diseases.