Urinary tract infection is a significant cause of morbidity in women throughout their
lifespan, in infant boys and in older men. Serious sequelae include frequent recurrences,
pyelonephritis with sepsis, renal damage in young children, pre-term birth, and
complications of frequent antimicrobial use including high-level antibiotic resistance and
Clostridium difficile colitis. High recurrence rates and increasing antimicrobial resistance
among uropathogens threaten to greatly increase the economic burden of this common
infection. In response, Dr. Scott Hultgren formed the Center for Women’s Infectious
Disease Research (cWIDR) at Washington University and, working with his SCORfunded
colleagues, developed an interdisciplinary UTI research program joining clinical
and basic science researchers to identify critical clinical questions, elucidate current
epidemiology, and identify specific disease-causing interactions between pathogens and
patients. Dr. Hultgren’s laboratory has developed novel models to study recurrent UTI in
women. Insights from Hultgren’s team have uncovered molecular details of how the most
common causative agent of UTI, uropathogenic E. coli (UPEC), uses a family of adhesive
fibers called Chaperone/Usher pili (CUP) to colonize the bladder and kidney. We have
dissected the structural basis of almost a dozen CUP pilus adhesins and elucidated their
role in host-pathogen interactions. Further, we have elucidated the structural basis of the
assembly of these virulence factors. For example, the human bladder is protected by a
crystalline array of mannosylated proteins known as uroplakins. The adhesin at the tip of
the type 1 pilus of E. coli, FimH, binds this mannosylated surface. The Hultgren
laboratory elucidated the structural basis of this FimH-mannose interaction, revealing how
UPEC mediates the first step of bladder tissue colonization and invasion). These molecular
Velcro-like interactions activate potent host defenses such as exfoliation of cells from the
bladder epithelium and influx of immune cells. Bacteria evade these host defenses, and
antibiotic treatment, by invading the bladder epithelium. Once inside host cells, they
rapidly multiply, forming transient biofilm-like intracellular bacterial communities (IBC)
that eventually disperse to establish quiescent intracellular reservoirs. These reservoirs can
then seed recurrent UTIs. A clinical collaboration with Dr. Thomas Hooton in Seattle
uncovered strong evidence that this IBC pathway occurs in humans a finding that might
account for many of the recurrent UTIs afflicting women. We uncovered complex
networks that determine disease outcome and predisposition to rUTIs. We have developed
novel models to study rUTI in women that reflect the two major risk factors for UTI in
humans; genetics and infection history. We found that an infection can leave an epigenetic
imprint leading to bladder mucosal remodeling. This re-programming of the bladder
predisposes the host to more severe rUTI upon subsequent bacterial exposure, even with
less pathogenic strains. This is leading to the dissection of what we term the gut-bladder
axis. Our basic science studies are being translated into novel clinical approaches for the
treatment and prevention of UTI. For example, working with structural biologists and
medicinal chemists, they have developed anti-adhesive mannosides that specifically block
UPEC’s ability to colonize the lower urinary tract by binding to FimH with several orders
of magnitude higher potency than the natural receptor. Our mannosides are currently being
tested in Phase1b human clinical trials. Based on the molecular dissection of pilus
assembly, our interdisciplinary research team has also designed pilicides that inhibit the
assembly of a broad class of bacterial adhesins. Further, we are working with the public
sector to develop a vaccine based upon the type 1 pilus adhesin, which is entering phase 2
human clinical trials. Trials have shown that this vaccine protects animals from recurrent
infection and has been allowed by the FDA for compassionate use. Each of these
therapeutic strategies offers a novel approach to the prevention and treatment of UTI, and
future clinical trials with these agents hold promise for reducing the suffering associated
with this extremely common condition. In summary, Dr. Hultgren’s interdisciplinary
research program has been very successful in spawning new insights and novel therapeutic
management strategies targeting UTIs.