The Role of Macrophages in Immune Responses to Giardia

摘要 蓝氏贾第鞭毛虫是世界上最常见的引起腹泻的原生动物。它感染了大约5亿人 世界各地的人们，经常导致营养吸收不良，这可能导致身体和认知 儿童的发育缺陷。矛盾的是，最近的数据也表明贾第虫的存在是 与儿童中中到重度腹泻水平的降低有关。感染通过以下途径传播： 摄取的包囊和囊壁含有大量的N-乙酰氨基半乳糖(GalNAc)聚合物。这个 巨噬细胞半乳糖结合凝集素(MGL)是识别GalNAc的主要凝集素。我们的 假设MGL对囊壁物质的识别在决定结果中起着重要作用 通过调节先天免疫反应和获得性免疫反应来控制感染。具体地说，我们假设 MGL1刺激巨噬细胞增强IL-10的产生 信号，如细菌的存在。这种IL-10可能会增强寄生虫的持久性，但也会限制 病理和降低疾病的严重程度。我们将利用体外培养解决这些假说。 MGL1缺陷小鼠来源的巨噬细胞。我们还将分析贾第虫感染情况，包括单独感染和 与另一种已知可引起小鼠严重炎症病理的寄生虫联合使用 缺乏MGL1以及缺乏巨噬细胞的小鼠。我们将分析寄生虫的负担和标志物 感染期间的病理学。骨髓嵌合体将被用来确定MGL1在特定细胞类型上的作用。

Abstract Giardia lamblia is the most common protozoan cause of diarrhea in the world. It infects ~500 million people worldwide, often resulting in nutrient malabsorption which can lead to physical and cognitive developmental defects in children. Paradoxically, recent data also indicate that the presence of Giardia is associated with reduced levels of moderate-to-severe diarrhea in children. The infection is transmitted by ingestion of cysts and the cyst wall contains large amounts of N-acetyl galactosamine (GalNAc) polymer. The macrophage galactose-binding lectin (MGL) is the dominant lectin capable of recognizing GalNAc. Our hypothesis is that recognition of cyst wall material by MGL plays a significant role in determining the outcome of infections by modulating both innate and adaptive immune responses. Specifically, we hypothesize that stimulation of macrophages through MGL1 potentiates the production of IL-10 in response to other activating signals such as the presence of bacteria. This IL-10 may enhance parasite persistence, but also limits pathology and decreases disease severity. We will address these hypotheses utilizing in vitro cultures of macrophages derived from MGL1 deficient mice. We will also analyze infections with Giardia, alone and in combination with another parasite known to induce severe inflammatory pathology in mice, using mice deficient in MGL1 as well as mice lacking macrophages. We will assay the parasite burdens and markers of pathology during infections. Bone marrow chimeras will be used to identify roles of MGL1 on specific cell types.