The Institute of Translational Medicine, Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin 300121, China; The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300071, China; TEDA Institute of Biological Sciences and Biotechnology, Tianjin Key Laboratory of Microbial Functional Genomics, Nankai University, Tianjin 300457, China.
The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300071, China; Department of Microbiology, College of Life Sciences, Nankai University, Tianjin 300071, China.
Cell Rep. 2022 Apr 19;39(3):110698. doi: 10.1016/j.celrep.2022.110698.
Urinary tract infections are predominantly caused by uropathogenic Escherichia coli (UPEC). UPEC infects bladder epithelial cells (BECs) via fusiform vesicles, escapes into the cytosol to evade exocytosis, and establishes intracellular bacterial communities (IBCs) for the next round of infection. The UPEC vesicle escape mechanism remains unclear. Here we show that UPEC senses host immune responses and initiates escape by upregulating a key phospholipase. The UPEC phospholipase PldA disrupts the vesicle membrane, and pldA expression is activated by phosphate reduction in vesicles. The host phosphate transporter PIT1 is located on the fusiform vesicle membrane, transporting phosphate into the cytosol. UPEC infection upregulates PIT1 via nuclear factor κB (NF-κB), resulting in phosphate reduction. Silencing PIT1 blocks UPEC vesicle escape in BECs, inhibits IBC formation in mouse bladders, and protects mice from UPEC infection. Our results shed light on pathogenic bacteria responding to intracellular phosphate shortage and tackling host defense and provide insights for development of new therapeutic agents to treat UPEC infection.
尿路感染主要由尿路致病性大肠杆菌（UPEC）引起。UPEC 通过梭形囊泡感染膀胱上皮细胞（BEC），逃入细胞质以逃避胞吐作用，并建立用于下一轮感染的细胞内细菌群落（IBC）。UPEC 囊泡逃逸机制尚不清楚。在这里，我们表明 UPEC 感知宿主免疫反应，并通过上调关键磷脂酶来启动逃逸。UPEC 磷脂酶 PldA 破坏囊泡膜，并且 pldA 表达受囊泡中磷酸盐减少的激活。宿主磷酸盐转运蛋白 PIT1 位于梭形囊泡膜上，将磷酸盐运入细胞质。UPEC 感染通过核因子 κB（NF-κB）上调 PIT1，导致磷酸盐减少。沉默 PIT1 可阻止 BEC 中 UPEC 囊泡逃逸，抑制小鼠膀胱中的 IBC 形成，并保护小鼠免受 UPEC 感染。我们的研究结果阐明了致病菌对细胞内磷酸盐缺乏的反应以及对宿主防御的应对机制，为开发新的治疗药物治疗 UPEC 感染提供了新的思路。
