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

Autor: Federico C. Beasley, Victor Nizet, Thomas J. Hannan, Scott J. Hultgren, Ann Lin, Nadia Keller, Robert A. Shalwitz, Joshua Olson
Rok vydání: 2014
Předmět:
medicine.medical_treatment
urologic and male genital diseases
Bacterial Adhesion
Piperazines
Cathelicidin
Uropathogenic Escherichia coli
Biology (General)
Escherichia coli Infections
Mice
Knockout
0303 health sciences
Protein Stability
female genital diseases and pregnancy complications
3. Good health
Anti-Bacterial Agents
Cytokine
Administration
Intravesical
Host-Pathogen Interactions
Urinary Tract Infections
Female
medicine.symptom
Research Article
Programmed cell death
QH301-705.5
Pyridones
Immunology
Antimicrobial peptides
Inflammation
Biology
Nitric Oxide
Microbiology
Cell Line
03 medical and health sciences
Immunity
Virology
Genetics
medicine
Animals
Humans
RNA
Messenger
Urothelium
Molecular Biology
Escherichia coli infection
030304 developmental biology
030306 microbiology
RC581-607
bacterial infections and mycoses
Hypoxia-Inducible Factor 1
alpha Subunit
Immunity
Innate
Mice
Inbred C57BL
Parasitology
Immunologic diseases. Allergy
Antimicrobial Cationic Peptides
Zdroj: PLoS Pathogens
PLoS Pathogens, Vol 11, Iss 4, p e1004818 (2015)
ISSN: 1553-7374
Popis: 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.
Author Summary Urinary tract infection (UTI), commonly caused by uropathogenic E.coli (UPEC), affects more than 150 million people worldwide, resulting in 14 million hospital visits per year and an estimated total cost of 6 billion dollars in direct health care. Due to the high prevalence of UTI and rapid emergence of antibiotic-resistant bacteria, new effective strategies to prevent and treat UTI are urgently needed. Here, we describe a global regulatory role of transcription factor hypoxia-inducible factor-1 (HIF-1) in innate antimicrobial defense against UPEC. HIF-1 stabilization reduces UPEC attachment to and invasion of uroepithelial cells, and protects bladders from UPEC-mediated cytotoxicity in vivo. In the murine UTI model, we found normal bladder HIF-1 expression is required for efficient UPEC clearance, since HIF-1-deficient mice suffer more severe infection than normal mice. Further studies showed that key elements of host protection provided by HIF-1 regulation are uroepithelial cell nitric oxide and antimicrobial peptide production. This study provides valuable insight into the importance of HIF-1 in supporting host immunity during UTI and its potential as a therapeutic target.
Databáze: OpenAIRE
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