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

Abstract

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.

Hypoxic regulation of neutrophil function and consequences for Staphylococcus aureus infection

“…Likewise, pharmacological HIF-1a stabilisation enhanced tissue neutrophil recruitment in mice treated with intradermal LPS [58]. Conversely, pharmacological HIF-1a stabilisation has been shown either to diminish neutrophil recruitment (in murine uropathogenic Escherichia coli bladder infection) [59], or to have no impact (in murine S. aureus skin infection) [60]. Recruitment of wildtype, HIF-1a-null or vHL-null neutrophils in a mouse model of group A Streptococcus ulcer was comparable up to 24 h [55].…”

Urinary Tract Infection: Pathogenesis and Outlook

“…, by sequestering siderophores and critical nutrients such as iron, from the bacteria) [51]. Other host transcriptional regulators such as hypoxiainducible factor 1α (HIF-1α) are also expressed in response to bacteria, potentially boosting innate defense components such as nitric oxide, cathelicidin, and β-defensin 2 [51, 52]. Recently, the humoral pattern recognition molecule pentraxin 3 (PTX3) was shown to help control UTI by serving as an opsonin and promoting bacterial uptake by neutrophils; UTI-prone children and adult cystitis patients who had suffered recurrent UTI as children exhibited polymorphisms in PTX3 [53], suggesting that the cellular and soluble components of innate immunity can influence disease outcomes.…”

Pharmacological Targeting of the Host–Pathogen Interaction: Alternatives to Classical Antibiotics to Combat Drug-Resistant Superbugs

“…Similarly acrophages and neutrophils deficient in the transcriptional regulator hypoxia-inducible factor-1 (HIF-1) have defects in glycolysis and ATP generation, leading to impaired microbicidal function and increased susceptibility of myeloid-specific HIF-1 knockout mice to infection [68]. Pharmacological stabilization of HIF-1 with a prolyl hydroxylase inhibitor drug (AKB-4924) to block its degradation pathway increased macrophage and neutrophil killing of MRSA and several Gram-negative bacterial pathogens, providing protection against skin and urinary tract infection in mouse challenge models [69, 70]. Mice in which deletion of C/EBPε mimics neutrophil-specific granule deficiency are hypersusceptible to S. aureus infection.…”