Urinary tract infections (UTIs) are very common with significant impacts on quality of life and health care costs. Urinary tract infections (UTIs) are one of the most common bacterial infections, causing considerable morbidity in females. Infection is highly recurrent despite appropriate antibiotic treatment. 50% of all women will have a UTI at some point in their lifetime. 20-40% of these women will suffer recurrences of UTI with serious deterioration in the quality of life including pain and discomfort, disruption of daily activities, increased healthcare costs, and few treatment options other than long-term antibiotic prophylaxis. In addition, serious sequelae such as renal scarring and sepsis can occur due to UTIs.

UTIs are also increasingly caused by antibiotic-resistant pathogens, leading to an increased use of fluoroquinolones and parenteral beta-lactams, which in turn has spawned a rise in resistance to these classes of antibiotics further exacerbating multidrug resistance (MDR). The Drug Resistance Index (DRI),  a composite measure that combines the ability of antibiotics to successfully treat infections with the extent of their use in clinical practice, shows that the number of UTIs posing treatment difficulties has been increasing since the mid-2000s. Uropathogenic E. coli (UPEC), including multidrug resistant UPEC (such as ST131), is the most common causative agent of both uncomplicated and complicated UTIs. Additionally, other pathogens have increased importance in complicated UTIs including Staphylococcus aureus (including methicillin-resistant S.aureus (MRSA)), Enterococcus spp (including vancomycin-resistant Enterococcus (VRE)), Klebsiella pneumoniae, and Acinetobacter spp. All of these are pathogens that can carry antibiotic resistance profiles deemed of concern by the CDC . The rise of antibiotic resistance within bacteria that cause UTIs is making it imperative that we find new therapeutic targets for this disease.

The Hultgren lab is using an interdisciplinary approach, combining clinical and basic science studies, to elucidate many aspects of UTIs including bacterial mechanisms important in disease, host response, disease outcomes, susceptibility markers, the impact of catheterization and avenues for the development of new therapeutics.We are grateful for research funding support from the National Institute of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and Office of Research on Women’s Health (ORWH).

 hires infect bladder COLOR

Urinary Tract Infection

In our interdisciplinary research program, we have combined clinical and basic science approaches to detail a highly complex acute pathogenic cycle for uropathogenic Escherichia coli (UPEC), the most common causative agent of UTIs and the host response to infection. Our work has led to an increased understanding of UTIs including molecular mechanisms of susceptibility, establishment and progression of disease, epidemiology and determination of factors that influence disease outcomes and sequelae.

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 FimA mut cultures

Uropathogenic E. coli (UPEC) genomics/genetics

UPEC are highly diverse. It has been well established that E. coli has a highly plastic genome capable of rapid alteration to facilitate survival in diverse environments. In addition, the role of host anatomy, physiology, and immune response may dramatically impact the susceptibility of individual strains of E. coli to colonize the host. Because of these factors, no specific genome structure or content has been identified that serves as a signature for the ability of E. coli to cause UTI.

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Chaperone/Usher Pathway (CUP) Pili

CUPs are ubiquitous in Gram-negative pathogens and are known to be critical virulence factors in a wide range of pathogenic bacterial genera, including Escherichia, Klebsiella, Acinetobacter, Pseudomonas, Haemophilus, Salmonella and Yersiniae. We have used the type 1 pili and P pili systems, which enable UPEC to cause bladder and kidney infections, respectively, as models to understand the assembly of CUP pili. We first discovered that P pili (and later type 1 and S pili) were multicomponent fibers, each consisting of a helical rod joined end to end to a linear tip fibrillum, which contains a two-domain adhesin at its distal end. Elucidating how these structures are built is uncovering basic principles of protein folding, chaperone function and macromolecular assembly.
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E. faecalis and fibrinogen co-localization picture is attached. Description: E. faecalis co-localized with fibrinogen on implanted mouse bladder during CAUTI. Nuclei in blue, mouse uroplakin III in red, fibrinogen in green and E. faecalis in purple.

Catheter associated UTIs (CAUTIs)

CAUTIs are the most common cause of hospital-associated infections (HAIs) in the US. According to the “Association for Professionals in Infection Control and Epidemiology”, >30 million Foley catheters are inserted annually in the United States, contributing to 1 million CAUTIs. Patient catheterization rates in acute care hospitals are estimated to be 10%, and in long-term care facilities estimated to range from 7.5% to 25%. Short-term urinary catheterization increases the risk of developing UTI and other complications up to 80%, and prolonged catheterization can increase the risk to 100%. Additionally, patients with catheter-associated bacteriuria have a 3% risk of bacteremia. While UPEC causes 85% of uncomplicated UTIs and 50% of CAUTI, other pathogens such as Enterococcus, Staphylococcus, Klebsiella and Acinetobacter are more common causes of CAUTI. Thus, given the prevalence and rising antibiotic resistance profiles of CAUTI-associated uropathogens, as well as the effect that catheterization has on the susceptibility to infection, we developed a mouse model of CAUTI, which mimics many of the features of clinical disease. Using this model we have elucidated aspects of E. faecalis CAUTI pathogenesis and demonstrated that EbpA, the adhesin of Ebp, which contains a metal ion-dependent adhesion site (MIDAS), is required for E. faecalis colonization in a catheter-implanted bladder. Further characterization of EbpA binding, along with determination of the pathogenic mechanisms by which E. faecalis causes disease, will aid in the identification of novel therapeutic targets for E. faecalis CAUTI.
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Bacterial amyloid (Curli) biogenesis

Fibrillar amyloid adhesins are an important and common structural motif in biofilm architecture. Many bacteria that form medically relevant biofilms, such as UPEC, enterohemorrhagic E. coli (EHEC), Salmonella spp., Citrobacter spp., and Mycobacterium tuberculosis produce amyloid fibers which can provide structural, adhesive and protective properties to a biofilm. Curli is one such amyloid fiber, produced by UPEC and Salmonella.
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Fibrous bacterial baskets in pellicles

Bacterial Community Interactions (Biofilms and Microbiome)

UPEC, like all bacteria exist in the host as part of a consortium of bacteria, which interact within clonal as well as mixed species communities. UPEC is able to form clonal biofilm-like intracellular bacterial communities (IBCs) within bladder epithelial cells, as well as on catheter material within the bladder.
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Gene expression in response to pilicides

Drugs and Vaccine Development

With dire predictions of antibiotic resistance reaching a tipping point, it is imperative that we develop novel, antibiotic-sparing medicines to avoid a future in which we face increasing deaths due to previously treatable common infections. We are focused on this mission by elucidating potential therapeutic targets in critical host-pathogen interactions for one of the most common infections in the United States, urinary tract infection (UTI), which has a significant economic toll on this country’s health system. UTIs are one of the most common afflictions of females with over 11 million women suffering from UTIs in the U.S. per year. Further, 20-30% of women diagnosed with a UTI will experience a recurrent UTI (rUTI) in the following months, resulting in a serious deterioration in quality of life through pain, discomfort, disruption of daily activities, and increased healthcare costs. This problem is being exacerbated by the rapid spread of antimicrobial resistance among uropathogenic Escherichia coli (UPEC), the cause of over 80% of UTIs. Patients suffering from a symptomatic UTI are commonly treated with broad-spectrum antibiotics. However, rates of antibiotic resistance are confounding UTI treatment for millions of women annually. Importantly, 25% of all adult sepsis cases can be traced back to the urinary tract. Improved treatments for UTI will therefore greatly reduce the incidence of sepsis, which increasingly involves multidrug resistant bacteria and is associated with an overall mortality rate of 20-40%. Thus, UTIs and UPEC are a “canary in the coal mine,” warning us of the coming antibiotic resistance crisis and the need for new antibiotic-sparing therapeutic strategies that can be developed by a deeper understanding of host-pathogen interactions
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