Immune Control of Giardia Pathogenesis

描述(申请人提供)：蓝氏贾第鞭毛虫是世界上最常见的引起腹泻的原虫。它感染了全球约5亿人，导致营养吸收不良，可能导致儿童认知发育缺陷。贾第鞭毛虫病的发病机制尚不清楚，阻碍了治疗和预防这种疾病的努力。数据表明，免疫反应通过诱导肠上皮细胞上的微绒毛缩短来促进病理，从而为营养吸收提供更大的表面积。我们的假设是，免疫反应通过对适配器蛋白Ezrin的翻译后调节来影响上皮细胞的细胞骨架。Ezrin连接质膜和肌动蛋白微丝，对微绒毛的正常形成是必不可少的。这项提议将利用小鼠和体外模型来测试对寄生虫的免疫反应是否会导致上皮细胞中Ezrin功能的变化。关键信号通路的作用以及用药物调节这些通路的能力也将被研究。 与公共卫生相关：贾第虫是美国最常见的原生动物腹泻原因，也被认为是生物防御B类威胁因子。这项提案中的研究将通过检查这种感染如何导致营养吸收不良，从而导致认知发育缺陷来改善公共健康。这些信息将为治疗常见疾病，如乳糜泻和炎症性肠病，以及腹泻疾病，如贾第鞭毛虫病提供新的战略。

DESCRIPTION (provided by applicant): Giardia lamblia is the most common protozoan cause of diarrhea in the world. It infects ~500 million people worldwide resulting in nutrient malabsorption which can lead to cognitive developmental defects in children. Mechanisms of pathogenesis in giardiasis are poorly understood, hindering efforts to both treat and prevent this disease. Data suggest that immune responses contribute to pathology by inducing shortening of the microvilli on intestinal epithelial cells that provide an enhanced surface area for nutrient absorption. Our hypothesis is that immune responses affect the epithelial cell cytoskeleton through post-translational regulation of the adaptor protein ezrin. Ezrin links the plasma membrane to actin microfilaments and is essential for proper formation of microvilli. This proposal will test determine if immune responses against the parasite lead to changes in the function of ezrin in epithelial cells using mouse and in vitro models. The role of key signaling pathways and the ability to modulate these pathways with pharmacologicals will also be investigated. PUBLIC HEALTH RELEVANCE: Giardia is the most common protozoan cause of diarrhea in the US and is also considered a Biodefense Category B threat agent. The studies in this proposal will improve public health by examining how this infection causes nutrient malabsorption that can lead to defects in cognitive development. This information will provide new strategies for treating common diseases like celiac disease and inflammatory bowel disease as well as diarrheal diseases like giardiasis.