Compounds targeting YadC of uropathogenic Escherichia coli and its host receptor annexin A2 decrease bacterial colonization in bladder
Xiao Li,
Geng Pei,
Lisong Zhang,
Yang Cao,
Jingyu Wang,
Lu Yu,
Wei Dianjun,
Shan Gao,
Zhi-Song Zhang,
Zhi Yao,
Quan Wang
Affiliations
Xiao Li
Department of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China
Geng Pei
Department of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China
Lisong Zhang
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Collaborative Innovation Center for Biotherapy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
Yang Cao
Department of Clinical Laboratory, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
Jingyu Wang
Department of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China
Lu Yu
Department of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China
Wei Dianjun
Department of Clinical Laboratory, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
Shan Gao
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Collaborative Innovation Center for Biotherapy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
Zhi-Song Zhang
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Collaborative Innovation Center for Biotherapy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
Zhi Yao
Department of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China; 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China
Quan Wang
Department of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China; Corresponding author.
Background: Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections (UTIs), and fimbrial tip adhesins, play important roles in UPEC colonization. Few fimbrial tip adhesins and their receptors on host cells, which have the potential to be the therapeutic targets, have been identified. Methods: the UPEC wild-type strain CFT073, ΔyadC and the complemented strain were used to perform assays in vitro and in vivo. The effects of D-xylose targeting YadC on UPEC colonization were evaluated. A YadC receptor was identified by far-western blotting, LC-MS/MS and co-immunoprecipitation. The effects of compounds targeting the receptor on UPEC colonization were tested. Findings: YadC was investigated for its mediation of UPEC adhesion and invasion to bladder epithelial cells in vitro; and its promotion of UPEC colonization in bladder in vivo. D-xylose, targeting YadC, showed prophylactic and therapeutic effects on UPEC colonization. Annexin A2 (ANXA2) was identified as a YadC receptor, involved in UPEC infection. ANXA2 inhibitors attenuated UPEC infections. The yadC gene was widely present in UPEC clinical isolates and phylogenetic analysis of yadC was performed. Interpretation: YadC and its receptor ANXA2 play important roles in UPEC colonization in bladder, leading to novel treatment strategies targeting YadC or ANXA2 for acute UTIs. Fund: This study was supported by grants from the National Natural Science Foundation of China (NSFC) Programs (31670071 and 31970133), the National Key Technologies R&D Program, Intergovernmental international innovation cooperation (2018YFE0102000), Tianjin Science and Technology Commissioner Project (18JCZDJC36000), the Science & Technology Development Fund of Tianjin Education Commission for Higher Education (2017ZD12). The Science Foundation of Tianjin Medical University (2016KY2M08). Keywords: Uropathogenic Escherichia coli, YadC, Annexin A2
