Boosting the ability of the urinary tract to fight infections
EMBARGO: April 30, 2015, 11am PDT / 2pm EDT
Urinary tract infections (UTIs) are common, and wide-spread antibiotic resistance has led
to urgent calls for new ways to combat these infections. A study published on April 30th in
PLOS Pathogens reports that 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, from the University of California, San Diego, USA, 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.
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 HIF1α 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 HIF1α.
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.
Please use this URL to provide readers access to the paper (Link goes live upon
article publication):
http://dx.plos.org/10.1371/journal. ppat.1004818
Press-Only Preview Of The Article:
https://www.plos.org/wp-content/uploads/2013/05/PATHOGENS_NIZET_APR30.pdf
Related Image for Press Use:
https://www.plos.org/wp-content/uploads/2013/05/PATHOGENS_NIZET_APR30_IMG.tif
Caption: 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
Contact:
Victor Nizet
e-mail: vnizet@ucsd.edu
phone: +1.858.534.7408
Authors and Affiliations:
Ann E. Lin, UC San Diego, USA
Federico C. Beasley, UC San Diego, USA
Joshua Olson, UC San Diego, USA
Nadia Keller, UC San Diego, USA
Robert A. Shalwitz, Aerpio Therapeutics, USA
Thomas J. Hannan, Washington University School of Medicine, USA
Scott J. Hultgren, Washington University School of Medicine, USA
Victor Nizet, UC San Diego, USA
Please contact plospathogens@plos.org if you would like more information.
Funding: The research was supported by NIH grants to VN (AI093451, AI057153, HD071600) and SJH
(DK098870, AI048689). AEL was supported by postdoctoral fellowships from the Canadian Institute of Health
Research and the American Association of Anatomists. RAS was an employee of Aerpio Therapeutics and
received salary support from the company. None of the grant funders nor Aerpio Therapeutics had a role in the
study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: RAS is an employee of Aerpio Therapeutics, which has sought to develop AKB-4924 for
its immunomodulatory properties in inflammatory bowel disease. This does not alter our adherence to all PLOS
policies on sharing data and materials.
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
About PLOS Pathogens
PLOS Pathogens is a peer-reviewed, open-access science journal that advances the understanding of bacteria,
fungi, parasites, prions, and viruses, and how these pathogens interact with their host organisms. For more
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