| First Author | Lin AE | Year | 2015 |
| Journal | PLoS Pathog | Volume | 11 |
| Issue | 4 | Pages | e1004818 |
| PubMed ID | 25927232 | Mgi Jnum | J:246050 |
| Mgi Id | MGI:5914319 | Doi | 10.1371/journal.ppat.1004818 |
| Citation | Lin AE, et al. (2015) Role of Hypoxia Inducible Factor-1alpha (HIF-1alpha) in Innate Defense against Uropathogenic Escherichia coli Infection. PLoS Pathog 11(4):e1004818 |
| abstractText | 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 alpha subunit (HIF-1alpha) in innate defense against UPEC-mediated UTI. The effects of AKB-4924, a HIF-1alpha 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-1alpha 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-1alpha 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 beta-defensin-2. We conclude that HIF-1alpha transcriptional regulation plays a key role in defense of the urinary tract against UPEC infection, and that pharmacological HIF-1alpha boosting could be explored further as an adjunctive therapy strategy for serious or recurrent UTI. |
