EVASION OF ANTIGEN PRESENTATION BY VACUOLAR PATHOGENS

描述（由申请人提供）：空泡病原体对宿主免疫系统提出了有趣的挑战。通过驻留在专门的细胞器中，它们可以逃避用于先天免疫检测和微生物抗原呈递的规范途径。为了了解对存在于独特液泡中的空泡病原体的免疫，我们使用呼吸道病原体嗜肺军团菌作为模型生物来解剖对免疫检测很重要的早期事件。军团菌有一种有趣的细胞内生活方式。它们居住在液泡中，最初避免与溶酶体融合，然后建立来自宿主内质网的液泡，支持细菌复制。为了进一步了解哺乳动物宿主对空泡病原体的反应，我们使用了在宿主运输中具有特定缺陷的军团菌突变体和缺乏在感染免疫中发挥作用的受体的突变小鼠。总体目标是确定模式识别受体在检测和清除嗜肺军团菌中的功能。Tlr信号对军团菌的反应将通过体内和体外试验进行研究。Nod蛋白家族成员在军团菌检测中的作用也将被讨论。重点将放在birc1e介导的反应如何限制军团菌的生长。

DESCRIPTION (provided by applicant): Vacuolar pathogens present interesting challenges to the host immune system. By residing in specialized organelles, they can evade canonical pathways used for innate immune detection and presentation of microbial antigens. To understand immunity to vacuolar pathogens that reside in unique vacuoles, we are using the respiratory pathogen Legionella pneumophila as a model organism to dissect early events that are important for immune detection. Legionella have an interesting intracellular lifestyle. They reside in a vacuole that initially avoids fusion with lysosomes, and then establish a vacuole derived from the host endoplasmic reticulum that supports bacterial replication. To further understand how mammalian hosts respond to vacuolar pathogens, we are using both Legionella mutants that have specific defects in host trafficking, and mutant mice that lack receptors that play a role in immunity to infection. The overall goal is to determine the function of pattern recognition receptors in the detection and clearance of Legionella pneumophila. Tlr signaling in response to Legionella will be investigated using in vivo and ex vivo assays. The role Nod protein family members play in Legionella detection will also be addressed. Emphasis will be placed on how Birc1e-mediated responses restrict Legionella growth.