尿路致病性大肠杆菌溶血素诱导ThGM-CSF分化加重肾脏损伤的免疫生物学机制

溶血素（HlyA）是尿路致病性大肠杆菌的一种重要毒力因子，当尿路感染（UTIs）发生时，HlyA可通过促进GM-CSF分泌加重肾脏损伤，但是对于GM-CSF的主要来源尚不清楚。CD4+T细胞来源的GM-CSF在多种炎症相关疾病中具有重要的调控作用。我们的预实验发现，尿路感染发生时，小鼠肾脏中选择性高表达GM-CSF的辅助性T细胞（ThGM-CSF）的比例显著升高，但对于ThGM-CSF是否在UTIs中发挥了作用尚无报道。本课题拟以野生CFT073和缺失HlyA的CFT073菌株分别感染小鼠，构建UTIs模型。以IL-1β诱导CD4+T细胞分化为ThGM-CSF作为切入点，利用CD4+T细胞选择性缺失GM-CSF的小鼠，研究HlyA对CD4+T细胞功能的影响，探讨ThGM-CSF的分化机制和T细胞来源的GM-CSF在UTIs中的作用，为UTIs的治疗以及预防患者组织损伤的形成提供新的策略。

Alpha-hemolysin (HlyA) is an important virulence factor of urinary pathogenic Escherichia coli (UPEC). In UTIs, HlyA can aggravate kidney damage by promoting the secretion of GM-CSF, but the main source of GM-CSF is still unclear. GM-CSF generated by CD4+T cells has an important regulatory role in various of inflammation-related diseases. Our preliminary data demonstrate that the proportion of a unique subset of T helper cells selectively expressing GM-CSF (ThGM-CSF) is significantly increased in UTIs, but there is no report if the group of cells played a role in UTIs. We will build UTIs model with UPEC wild strain CFT073 and deletion HlyA strain (ΔhlyA). As the entry point, IL-1β can stimulate CD4+T cells to differentiate into ThGM-CSF. By using T cell selectivity GM-CSF-deficient mice, we will further study the effect of HlyA on CD4+T cell function in UTIs. Meanwhile, we will explore the differentiation mechanism of ThGM-CSF and the role of T cell-derived GM-CSF in urinary tract infections. The proposed studies will provide new strategies for treatment of UTIs and preventing further tissue damage in patients with UTIs.