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A Novel Immunity Boosting Strategy through Hypoxia‐Inducible Factor‐1 (HIF‐1) against Urinary Tract Infections
Author(s) -
Lin Ann,
Beasley Federico,
Olson Joshua,
Keller Nadia,
Shalwitz Robert,
Hannan Thomas,
Hutlgren Scott,
Nizet Victor
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.558.7
Subject(s) - innate immune system , antimicrobial , urinary system , cathelicidin , microbiology and biotechnology , immunology , inflammation , antibiotic resistance , antimicrobial peptides , biology , immune system , antibiotics , medicine , endocrinology
Uropathogenic E. coli (UPEC) is the primary cause of urinary tract infections (UTI), affecting approximately 150 million people worldwide. Hypoxia‐inducible factor‐1 a (HIF‐1α) is a master transcription regulator that coordinates gene expression involving innate immunity. Here, we hypothesize HIF‐1α is important in mounting innate defense against UPEC‐mediated UTI. We used AKB‐4924, a HIF‐1α stabilizing agent, to examine its impact on human uroepithelial cells HTB‐9 and C57BL/6 mice during UPEC infection. UPEC adherence and invasion were significantly compromised in HTB‐9 cells with accumulated HIF‐1α protein. Moreover, cells treated with AKB‐4924 suffered significantly reduced cell death and exfoliation. Likewise, less UPEC was recovered from urine, bladders and kidneys of AKB‐4924 treated mice, whereas more bacteria were recovered from bladders with HIF‐1α deletion. Bladders and kidneys of AKB‐4924 treated mice developed less inflammation marked by decreases in pro‐inflammatory cytokine release and neutrophil activity assessed by ELISA, myeloperoxidase and immunolocalization assays. We also found AKB‐4924 treatment lead to an enhanced production of nitric oxide and antimicrobial peptides cathelicidin and β‐defensin 2. This is the first to report that HIF‐1α boosting of antimicrobial productions in uroepithelial cells is an essential defense strategy for bacterial resistance in the urinary tract.