Uropathogenic Escherichia coli invades bladder epithelial cells by activating kinase networks in host cells

Abstract

Uropathogenic (UPEC) is the causative bacterium in most urinary tract infections (UTIs). UPEC cells adhere to and invade bladder epithelial cells (BECs) and cause uropathogenicity. Invading UPEC cells may encounter one of several fates, including degradation in the lysosome, expulsion to the extracellular milieu for clearance, or survival as an intracellular bacterial community and quiescent intracellular reservoir that can cause later infections. Here we considered the possibility that UPEC cells secrete factors that activate specific host cell signaling networks to facilitate the UPEC invasion of BECs. Using GFP-based reporters and Western blot analysis, we found that the representative human cystitis isolate UTI89 and its derivative UTI89ΔFimH, which does not bind to BECs, equally activate phosphatidylinositol 4,5-bisphosphate 3-OH kinase (PI3K), Akt kinase, and mTOR complex (mTORC) 1 and 2 in BECs. We also found that conditioned medium taken from UTI89 and UTI89ΔFimH cultures similarly activates epidermal growth factor receptor (EGFR), PI3K, Akt, and mTORC and that inhibition of EGFR and mTORC2, but not mTORC1, abrogates UTI89 invasion and in animal models of UTI. Our results reveal a key molecular mechanism of UPEC invasion and the host cells it targets, insights that may have therapeutic utility for managing the ever-increasing number of persistent and chronic UTIs.

Virulence Potential of a Multidrug-Resistant Escherichia coli Strain Belonging to the Emerging Clonal Group ST101-B1 Isolated from Bloodstream Infection

“…The ExPEC prototype strains CFT073, 536, J96, and RS218 belong to phylogroup B2, and all showed the phenotypic capacity to adhere to and invade a variety of epithelial cells, survival the complement bactericidal activity, and produce biofilms [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Nevertheless, these features were expressed at different levels in clinical isolates [ 22 , 26 , 27 ].…”

Dissecting and Evaluating the Therapeutic Targets of Coptis Chinensis Franch in the Treatment of Urinary Tract Infections Induced by Escherichia coli

“…IL6 is known as an inflammatory biomarker, while FOS, MYC, and EGFR were originally known as oncogenes. Recently, a growing number of studies have revealed that these oncogenes might play key regulation roles in inflammation and immune responses ( Wagner, 2010 ; Schonthaler et al, 2011 ; Man and Kallies, 2015 ; Kim et al, 2018 ; Fajgenbaum and June 2020 ). Therefore, the four targets may be responsible for the action of CCF against UTIs.…”

The immune responses to different Uropathogens call individual interventions for bladder infection

“…In the bladder of mice lacking RNase 7 and LL-37, the UPEC communities are significantly increased (47,63). (Figure 1) Some UPEC survives from the extracellular immune responses and invades BECs, which then initiate the intracellular efflux immune responses (65,66). Once BECs are invaded, two waves of UPEC expulsion in an innate immune signaling-orchestrated process occur (67).…”