David Klumpp, PhD Assistant Professor Urology Molecular Pathogenesis of Urinary Tract Infections Curricula: Immunology and Microbial Pathogenesis E-mail:   d-klumpp@northwestern.edu

Our laboratory currently pursues two major areas of interest that involve microbiology, immunology, neuroscience, and have implications for cancer. One major focus of the lab is the pathogenesis of urinary tract infections (UTIs). UTIs are the second most common infectious disease, behind only respiratory tract infections, and are caused by uropathogenic E. coli (UPEC). UPEC have larger genomes than laboratory strains of E. coli, and this extra DNA is thought to encode virulence factors that are necessary for execution of the pathogenic program and survival in the host environment. We have found that UPEC strains suppress bladder cell inflammatory responses by inhibiting activation of a critical transcription factor, NFkB, and we are now developing genetic screens to identify the virulence factor(s) underlying this suppressive activity. Current and future work also involves determining how the inhibition of inflammatory responses potentiates apoptosis and how immune responses are altered by UPEC to extend the window of pathogenic opportunity.

The second major area of interest is how neural circuits can induce bladder inflammation by activating the innate immune response. A long-standing hypothesis for the pathogenesis of a particular bladder disease (interstitial cystitis, IC) is that substance P-containing nerves stimulate mast cells that, in turn, release factors that induce bladder inflammation and also feedback to further stimulate substance P nerves. Using a culture model, we demonstrated that mast cells directly induce urothelial inflammation by releasing tumor necrosis factor (TNF). We are currently extending these findings by inducing neurogenic bladder inflammation in mice using a neurotropic virus, and we observe a TNF-dependent apoptosis of urothelial cells that resembles the bladder lesions of IC patients. Current and future work involves the use of transgenic and mast cell-deficient mouse strains to determine the involvement of specific immune cells and neural signals in mediating neurogenic bladder inflammation.

Publications:

Batler RA, Sengupta S, Forrestal SG, Schaeffer AJ, Klumpp DJ. Mast cell activation triggers a urothelial inflammatory response mediated by tumor necrosis factor-alpha. J Urol. 2002 Aug;168(2):819-25.

Klumpp DJ, Forrestal SG, Karr JE, Mudge CS, Anderson BE, Schaeffer AJ. Epithelial differentiation promotes the adherence of type 1-piliated Escherichia coli to human vaginal cells. J Infect Dis. 2002 Dec 1;186(11):1631-8

Klumpp DJ, Weiser AC, Sengupta S, Forrestal SG, Batler RA, Schaeffer AJ. Uropathogenic Escherichia coli potentiates type 1 pilus-induced apoptosis by suppressing NF-kappaB. Infect Immun. 2001 Nov;69(11):6689-95.