The Role of Macrophages in Immune Responses to Giardia

摘要 贾第虫是世界上最常见的引起腹泻的原生动物。它感染了~ 5亿 世界各地的人们，往往导致营养吸收不良，这可能导致身体和认知 儿童的发育缺陷。巧合的是，最近的数据也表明，贾第虫的存在是 与儿童中度至重度腹泻水平降低有关。感染是通过 食入包囊后，包囊壁含有大量的N-乙酰半乳糖胺（GalNAc）聚合物。的 巨噬细胞半乳糖结合凝集素（MGL）是能够识别GalNAc的主要凝集素。我们 假设MGL对囊壁物质识别在决定结果中起重要作用 通过调节先天性和适应性免疫反应来控制感染。具体来说，我们假设， 通过MGL 1刺激巨噬细胞可增强IL-10的产生， 信号，如细菌的存在。这种IL-10可以增强寄生虫的持久性，但也限制了 病理学和降低疾病的严重程度。我们将利用体外培养来解决这些假设， 来自MGL 1缺陷小鼠的巨噬细胞。我们还将分析贾第虫感染，单独和 与另一种已知在小鼠中诱导严重炎症病理学的寄生虫组合，使用小鼠 缺乏MGL 1的小鼠以及缺乏巨噬细胞的小鼠。我们将分析寄生虫负荷和 感染期间的病理学。骨髓嵌合体将用于鉴定MGL 1对特定细胞类型的作用。

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.