Urinary tract infections are common and wide-spread antibiotic resistance has led to calls for new ways to combat these infections. A recent paper details an experimental drug that stabilizes the human immune defense protein HIF-1α can protect human bladder cells and mice against a major UTI pathogen, and it might provide a therapeutic alternative or complement to antibiotic treatment.
HIF-1α is known to play a key role in modulating the innate (non-specific) immune response, which is the body's first line of defense against intruding pathogens. Like many regulator proteins, HIF-1α is relatively short-lived. To increase HIF-1α levels, researchers have developed drugs that delay its break-down.
Such HIF-1α stabilizers are in clinical development for treatment of anemia, and in this study Victor Nizet and colleagues explored the potential use of these drugs as "innate immune boosters" against uropathogenic E.coli (UPEC) bacteria that are a major cause of UTIs.
Compared with UPEC-infected control mouse bladders (vehicle), bladders treated with the HIF-1alpha stabilizer (AKB-4924) express higher levels of the defense molecule CRAMP (red). Credit: Nizet et al., CC-BY
In human urinary tract cells, treatment with the drugs indeed increased HIF-1α levels in healthy cells. Such cells were then more resistant to UPEC attachment, as well as subsequent invasion and killing by the bacteria, than human urinary tract cells with normal HIF-1α levels.
Using an established mouse UTI model, the researchers showed that administration of HIF-1α stabilizers directly into the bladder protected the mice against UPEC infection of the bladder and kidney. They also found that invasion of bladder cells, a critical early step in the infection process, was reduced in treated mice compared to untreated ones.
To verify the importance of HIF-1α in the defense against UPEC infection, the researchers studied mutant mice with much reduced HIF-1α levels. Exposed to UPEC, these mice were more susceptible to bladder infection, and pre-treatment with HIF-1α stabilizers made no difference. This demonstrates that the drugs attenuate UTIs through their effect on HIF-1α.
Finally, the researchers examined whether treatment with HIF-1α stabilizers would be beneficial even against an established UTI. To do this, they infected mice with UPEC first and then administered the drugs into the bladder 6 hours later. The treated mice had a more than 10-fold reduced rate of bladder colonization, demonstrating that HIF-1α stabilization is beneficial even after the initial infection.
The researchers conclude that their "combined data indicate that by stabilizing HIF-1α, AKB-4924 [the specific HIF-1α stabilizer they used] enhances production of antimicrobial effectors in both prophylactic and therapeutic settings, promoting bacterial clearance, and suggesting HIF-1α boosting as a potential adjunctive therapeutic strategy in UTI management." The next steps include testing HIF-1α stabilizers in a clinical trial setting in humans, and making versions of the drug that can be taken orally and reach the urinary tract.
Citation: Lin AE, Beasley FC, Olson J, Keller N, Shalwitz RA, Hannan TJ, et al. (2015) Role of Hypoxia Inducible Factor-1α (HIF-1α) in Innate Defense against Uropathogenic Escherichia coli Infection. PLoS Pathog 11(4): e1004818. doi:10.1371/journal.ppat.1004818