Work in our group focuses on the structural molecular biology of bacterial cell surfaces & host-pathogen interactions. For most pathogenic bacteria, a crucial initial step in the establishment of infection is the recognition and colonization of the host tissue by specific attachment via surface-exposed adhesion molecules. In gram-negative bacteria, these adhesins are displayed on the outer membrane as single proteins (e.g. autotransporters or two-partner secretion systems) or can be incorporated into filamentous polymers (chaperone/usher pili, type II pili, type IV secretion pili and curli). Adhesin-mediated attachment can simply serve as a means of avoiding clearance through mechanical shear, or can trigger more complex host responses like cytoskeleton reorganization and cell invasion, or provide the required proximity to the host cell to enable other virulence mechanisms to come into action (e.g. effector injection through type III and type IV secretion systems). In an era of increased antibiotics resistance and difficulties in controlling hospital-acquired infections, it is essential to gain a better understanding of the fundamental principles governing the infection process. Our lab studies the structural molecular biology of bacterial adhesins and cell-surface filaments with respect to their function in bacterial pathogenesis, with the ultimate aim of developing a new generation of virulence-targeted antimicrobials.
Helicobacter pylori Adhesion - Countering a life-long attachment to the host
Due to its extreme persistence in the host and the known involvement of a complex adherence profile in maintaining infection, Helicobacter forms the ideal proof-of-principle case for the development of anti-adhesin drugs. Mounting evidence shows that the presence of only a selected number of virulence factors is associated with disease-causing HP strains, responsible for peptic ulceration and an increased risk for gastric cancers. The development of anti-virulence therapies targeting HP adhesins has the potential for the broad-scale selective clearance of pathogenic HP strains only.
Chaperone/Usher Pilus Assembly - Towards selective disarmament of adhesive fibers
P and type 1 pili are responsible for the early onset and persistence of UPEC-caused urinary tract infections (UTIs) by mediating attachment to the kidney epithelium (P pili) or attachment and invasion of the bladder epithelium cells (type 1 pili), respectively. They are assembled by the conserved chaperone/usher (CU) pathway, responsible for the biogenesis of more than 100 surface organelles in many other important human pathogens (including Yersinia, Salmonella, Shigella, Haemophilus). Two strategies are investigated for countering pilus-mediated disease processes: (1) anti-adhesive compounds targeted against the adhesive sub-units (2) pilus biogenesis inhibitors.
Curli - Structural biology of controlled amyloid deposition
Curli are proteinaceous filaments found on the surfaces of E. coli and Salmonella species where they mediate biofilm formation and have been shown to bind a range of human plasma and contact-phase proteins. Curli fibers exhibit typical characteristics of amyloids. Contrary to what is seen in human pathogenic amyloid depositions, curli formation follows a controlled biosynthetic pathway involving several protein co-factors that prevent premature aggregation and guide sub-unit passage through the bacterial periplasm and outer membrane. We study the structural molecular biology of curli biosynthesis as a model system for controlled amyloid deposition and as a route towards future nanobiotechnological applications.
- A bacterial glycosidase enables mannose-6-phosphate modification and improved cellular uptake of yeast-produced recombinant human lysosomal enzymes. (Nat Biotechnol, 30, 1225-31, 2012)
- SbsB structure and lattice reconstruction unveil Ca2+ triggered S-layer assembly. (Nature, 487, 119-22, 2012)
- Crystal structure of the FimD usher bound to its cognate FimC-FimH substrate. (Nature, 474, 49-53, 2011)
- Architectures and biogenesis of non-flagellar protein appendages in Gram-negative bacteria. (EMBO J, 27, 2271-80, 2008)
- Fiber formation across the bacterial outer membrane by the chaperone/usher pathway. (Cell, 133, 640-52, 2008)