Role of Hypoxia Inducible Factor-1α (HIF-1α) in Innate Defense against Uropathogenic Escherichia coli Infection

PLoS Pathogens

Robert A. Shalwitz¹  Scott J. Hultgren²  Victor Nizet³  Thomas J. Hannan³  Joshua Olson⁴  Ann E. Lin⁴  Federico C. Beasley⁴  Nadia Keller⁴ 

[1] Aerpio Therapeutics, Cincinnati, Ohio, United States of America;Center for Women’s Infectious Disease Research, Washington University School of Medicine, St. Louis, Missouri, United States of America;Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America;Division of Pediatric Pharmacology & Drug Discovery, University of California, San Diego, La Jolla, California, United States of America

关键词: Bladder;    Urinary tract infections;    Inflammation;    Cytokines;    Nitrites;    Nitric oxide;    Mouse models;    Kidneys;   

DOI  :  10.1371/journal.ppat.1004818

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Uropathogenic E. coli (UPEC) is the primary cause of urinary tract infections (UTI) affecting approximately 150 million people worldwide. Here, we revealed the importance of transcriptional regulator hypoxia-inducible factor-1 α subunit (HIF-1α) in innate defense against UPEC-mediated UTI. The effects of AKB-4924, a HIF-1α stabilizing agent, were studied using human uroepithelial cells (5637) and a murine UTI model. UPEC adherence and invasion were significantly reduced in 5637 cells when HIF-1α protein was allowed to accumulate. Uroepithelial cells treated with AKB-4924 also experienced reduced cell death and exfoliation upon UPEC challenge. In vivo, fewer UPEC were recovered from the urine, bladders and kidneys of mice treated transurethrally with AKB-4924, whereas increased bacteria were recovered from bladders of mice with a HIF-1α deletion. Bladders and kidneys of AKB-4924 treated mice developed less inflammation as evidenced by decreased pro-inflammatory cytokine release and neutrophil activity. AKB-4924 impairs infection in uroepithelial cells and bladders, and could be correlated with enhanced production of nitric oxide and antimicrobial peptides cathelicidin and β-defensin-2. We conclude that HIF-1α transcriptional regulation plays a key role in defense of the urinary tract against UPEC infection, and that pharmacological HIF-1α boosting could be explored further as an adjunctive therapy strategy for serious or recurrent UTI.

【 授权许可】

CC BY