Targeting Host Tyrosine Kinase Receptor EPHA2 Signaling Affects Uropathogen Infection in Human Bladder Epithelial Cells

Abstract

Urinary tract infections (UTIs) affect a major proportion of the world population but have limited non-antibiotic-based therapeutic and preventative strategies against UTIs. Facultative intracellular uropathogens such as strains of uropathogenic E. coli, K. pneumoniae, E. faecalis, E. cloacae are well-known uropathogens causing UTIs. These pathogens manipulate several host-signaling pathways during infection, which contributes to recurrent UTIs and inappropriate antibiotic application. Since host cell receptor tyrosine kinases (RTKs) are critical for the entry, survival and replication of intracellular pathogens, we investigated whether different uropathogens require host EPHA2 receptors for their intracellular survival using a cell culture model of intracellular infection in human bladder epithelial cells (BECs). Infection of BECs with seven different uropathogens enhanced the expression levels and activation of EPHA2. The significance of EPHA2 signaling for uropathogen infection was investigated by silencing EPHA2 expression using RNA interference or by inhibiting the kinase activity of EPHA2 using small-molecule compounds such as dasatinib or ALW-II-41-27. Both preventive and therapeutic tyrosine kinase inhibition significantly reduced the intracellular bacterial load. Thus, our results demonstrate the involvement of host cell EPHA2 receptor during intracellular uropathogen infection of BECs, and targeting RTK activity is a viable non-antibiotic therapeutic strategy for managing recurrent UTIs.