Scott J. Hultgren, Ph.D.

Helen L. Stoever Professor
Molecular Microbiology

Molecular Microbiology and Microbial Pathogenesis Program
Plant and Microbial Biosciences Program
Biochemistry, Biophysics, and Structural Biology Program
Molecular Cell Biology Program

  • 314-362-6772

  • 314-747-3627

  • 314-362-7042

  • 314-362-1998

  • 10260 McDonnell Pediatric Research Building

  • hultgren@wustl.edu

  • http://www.hultgrenlab.wustl.edu

  • antibiotic-sparing therapeutics, host-pathogen interactions, bacterial pathogenesis, drug and vaccine development, multi-drug resistant E. coli, MRSA, Enterococcus, Acinetobacter, Klebsiella, urinary tract infections (UTI)

  • Interdisciplinary approach combining genetics, genomics, biochemistry, structural biology, high-resolution imaging, animal models, clinical studies and combinatorial chemistry to determine key aspects of bacterial pathogenesis and apply our knowledge to development of new therapeutics.

Research Abstract:

My lab uses an interdisciplinary approach combining genetics, genomics, biochemistry, structural biology, high-resolution imaging, animal models, clinical studies and combinatorial chemistry to determine key aspects of bacterial pathogenesis and then apply our knowledge to the development of new therapeutics, which is increasingly more critical as antibiotic resistance increases. We have elucidated many key molecular details of chaperone usher pathway (CUP) pilus assembly and adhesin interactions critical in a variety of Gram-negative bacterial infections. We have developed multiple mouse models of UTI, which not only reflect many aspects of differential clinical outcomes, but also predict pathophysiological measures subsequently confirmed in humans. We elucidated the structural basis of interactions between the type 1 pilus adhesin, FimH, with its mannose receptor, revealing how UPEC mediates the first step of bladder tissue colonization and invasion. This initial invasion into host cells, begins a pathogenic cycle in which UPEC rapidly multiply, forming transient biofilm-like intracellular bacterial communities (IBC) of ~10^^4 cells, then detach from these IBCs and flux out of the host cell. Once in the lumen they can invade new host cells and repeat the cycle perpetuating the acute infection. This acute infection can either self-resolve or develop into chronic cystitis that lasts the lifetime of the animal unless cleared by antibiotic treatment. Importantly, we found that a history of chronic cystitis leaves an epigenetic imprint on the bladder tissue and is a significant risk factor for a subsequent recurrence of severe chronic cystitis. Understanding how prior infection influences a new infection is needed in order to understand clinical recurrent UTI. In addition, we have developed a mouse model of catheter-associated UTI (CAUTI) and elucidated: i) critical aspects of host-pathogen interactions that contribute to the Enterococcus faecalis and S. aureus CAUTI; ii) the mechanism of E. faecalis pilus biogenesis; iii) fundamental aspects of enterococcal and staphylococcal biofilm formation and; iv) nutritional requirements during CAUTI. 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. We have translated our basic findings developing vaccines and anti-adhesive small molecules. For instance, 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 holds promise for reducing rUTI. Together, our work is changing the way UTIs are evaluated, re-shaping models of bacterial infections in general and spawning new technologies to design novel anti-microbial therapeutics to treat and/or prevent UTIs.

Mentorship and Commitment to Diversity Statement:
Dr. Hultgren has trained over 70 individuals most of whom have moved on to successful careers in academia and industry. Additionally, over the years he has developed a deep and rich network of collaborators all over the world that his trainees will have access to. He encourages his students and postdoctoral fellows to follow their own ideas and approaches, in order to lead them to new and exciting areas. His philosophy is to give credit to his mentees and to altruistically promote their career advancement on ideas and work spawned in the laboratory under his mentorship. Thus, he works to reward his mentees for their work, for their thirst for generating ideas and making discoveries, always trying to give them the credit and then subsequently working to foster their career development. He also continuously exposes his trainees to collaborators with expertise outside of his own, thus allowing them to expand their horizons. He then strongly encourages his trainees to take responsibility of new enterprises, which fosters their growth, maturation, and career development. His trainees are also encouraged to pursue their interests, even when it comes at a cost to his own research program, as they develop their careers and to pursue new approaches and new ideas and to follow up on unexpected results. His intent is to create an atmosphere where students and postdocs become hungry for knowledge, seeking creative approaches to elucidate complex networks in host-pathogen interactions and acquiring whatever expertise is necessary to answer the key questions.

Selected Publications:

Spaulding CN, Klein RD, Ruer S, Kau AL, Schreiber HL, Cusumano ZT, Dodson KW, Pinkner JS, Fremont DH, Janetka JW, Remaut H, Gordon JI, Hultgren SJ. Selective depletion of uropathogenic E. coli from the gut by a FimH anatagonist. Nature 2017. 546(7659):528-532. PMCID: PMC565459.

O'Brien VP, Hannan TJ, Yu L, Livny JL, Roberson EDO, Schwartz DJ, Souza S, Mendelsohn CL, Colonna M, Lewis AL, Hultgren SJ. A mucosal Imprint left by prior Escherichia coli bladder infection sensitizes to recurrent disease. Nature Microbiol. 2016. 2:16196. PMCID: PMC5308540

Langermann S, Palaszynski S, Barnhart M, Leath S, Auguste G, Pinkner J, Barren P, Koenig S, Jones CH, and Hultgren SJ: Prevention of Mucosal Escherichia coli. infection by FimH-adhesin-based systemic vaccination. Science 1997. 276:607-611. PMID: 9110982.

Omattage NS, Deng Z, Pinkner JS, Dodson KW, Almqvist F, Yuan P, Hultgren SJ. Structural basis for usher activation and intramolecular subunit transfer in P pilus biogenesis in Escherichia coli. Nat Microbiol. 2018. 3(12):1362-1368. PMCID PMC6258349.

Anderson GG, Palermo JJ, Roth R, Heuser J, and Hultgren SJ. Intracellular bacterial biofilm-like pods in urinary tract infections. Science 2003. 301:105-107. PMID: 12843396.

Last Updated: 12/10/2021 4:38:54 PM

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