Hultgren Lab Research
The work in the Hultgren lab elucidates the structure, function and mechanism of action of bacterial factors involved in host pathogen interactions, host responses and bacterial subversion mechanisms that facilitate persistence in the host. Our studies blend a powerful genetic system with X-ray crystallography, animal models, cell biology, biochemistry, high-resolution electron and video microscopy, functional genomics and immunology. These approaches allowed us to discover the basis of a molecular machine found in diverse gram-negative pathogens, including Escherichia coli, called the chaperone/usher pathway. This pathway is responsible for the assembly of pili, adhesive fibers that participate in host-pathogen interactions. We have also discovered that E. coli produce amyloid-like fibers called curli. Fundamental questions about the structural basis of the protein-protein interactions involved in amyloid formation are being addressed in this system. This work will provide clues to the structure and function of curli and have implications for the pathology of Alzheimer's and other amyloid diseases.
We also use a multidisciplinary approach to investigate the function of these fibers and other virulence factors in the pathogenesis of uropathogenic E. coli (UPEC). Our studies have changed the clinical paradigm of urinary tract infections (UTIs) and are leading to new and better treatments and clinical diagnoses. We solved the structural basis of how pilus adhesins of UPEC recognize receptors on uroepithelial cells, and discovered an elaborate network of molecular cross-talk that occurs as a consequence of these interactions. Our work revealed that UPEC virulence depends on invasion into the superficial umbrella cells of the bladder where the bacteria rapidly replicate and form intracellular biofilms that we have termed pods. The intracellular biofilm protects the bacteria from host responses and antibiotics, thus allowing the bacteria to persist. We have sequenced the UPEC genome and are currently using a multitude of approaches to try to understand the molecular basis of chronicity and recurrence. This work is spawning new technologies to design novel vaccines and anti-microbial therapeutics that will block the ability of bacteria to adhere to host tissues, and thus prevent their ability to establish infections.