Research

Urinary tract infections (UTIs) are very common with significant impacts on quality of life and health care costs. 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 studying many aspects of UTIs including bacterial mechanisms important in disease, host response, disease outcomes, susceptibility markers, 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

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. Disturbingly, multi-drug resistant uropathogens are becoming more prevalent and globally distributed making UTI an increasingly pressing public health concern.
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 FimA mut cultures

UPEC Genetics/Genomics

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. We have completed the full genome sequence of multiple urinary and fecal E. coli isolates and are analyzing this data to better understand UPEC pathogenesis requirements.
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Chaperone/Usher Pathway (CUP) Pili

Extracellular fibers called chaperone-usher pathway (CUP) pili are critical virulence factors in a wide range of pathogenic Gram-negative bacteria. Today, with genome sequencing and varied infection models, we now know that this is a wide-spread family of hundreds of different extracellular fibers, many with essential adherence functions in various niches and body habitats and/or in biofilm formation in diverse Gram-negative bacteria including E. coli, Klebsiella, Pseudomonas, Haemophilus, Salmonella and Yersiniae. We use 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.
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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.

Enterococcal pathogenesis/catheter-associated UTI

Catheter-associated urinary tract infections (CAUTIs) are one of the most common nosocomial infections and if untreated can lead to serious complications including bacteremia and death. Enterococcus faecalis is a leading causative agent of CAUTI and prevention and treatment are hindered by its ability to adhere to and persist within the host and on hospital surfaces. Furthermore, E. faecalis is inherently resistance to many antimicrobials, and there is increasing prevalence of strains resistant to multiple antibiotics. E. faecalis can form biofilms on indwelling medical devices, such as urinary catheters, and grow despite a robust inflammatory response.
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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. In addition, UPEC can thrive within the host on periurethral surfaces and within the gastrointestinal tract, sites as part of a diverse bacterial microbiota. In order to understand UPECs ability to survive and replicate within these environments we have developed a number of in vitro monoculture biofilm models and we have studied factors that allow UPEC to colonize the gut in combination with differing gut bacterial communities.
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Gene expression in response to pilicides

Drugs and Vaccine Development

While antibiotic therapy has been resoundingly successful in treating acute UTI, recent increases in the prevalence of resistance to first-line empiric therapies such as trimethoprim-sulfamethoxazole (TMP-SMZ) are leading to frequent use of fluoroquinolones as first line therapy for UTI. Further, multi-drug resistant strains threaten to make chronic/recurrent UTI an even more common problem. Thus, understanding the mechanisms contributing to acute UTI and progression to chronic and/or recurrent UTI is of critical clinical importance. Our work has led to targeted development of therapeutic molecules, which block CUP pilus assembly or function.
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