Abstract
During urinary tract infection (UTI), the second most common bacterial infection, dynamic interactions take place between uropathogenic E. coli (UPEC) and host urothelial cells. While significant strides have been made in the identification of the virulence factors of UPEC, our understanding of how the urothelial cells mobilize innate defenses against the invading UPEC remains rudimentary. Here we show that mouse urothelium responds to the adhesion of type 1-fimbriated UPEC by rapidly activating the canonical NF-κB selectively in terminally differentiated, superficial (umbrella) cells. This activation depends on a dual ligand/receptor system, one between FimH adhesin and uroplakin Ia and another between lipopolysaccharide and Toll-like receptor 4. When activated, all the nuclei (up to 11) of a multinucleated umbrella cell are affected, leading to significant amplification of proinflammatory signals. Intermediate and basal cells of the urothelium undergo NF-κB activation only if the umbrella cells are detached or if the UPEC persistently express type 1-fimbriae. Inhibition of NF-κB prevents the urothelium from clearing the intracellular bacterial communities, leading to prolonged bladder colonization by UPEC. Based on these data, we propose a model of dual ligand/receptor system in innate urothelial defenses against UPEC.
Highlights
Responses in this pathway in genetically engineered mice lacking key nuclear factor-κ B (NF-κ B) pathway components can result in persistent inflammatory or infectious states[8]
While PBS-inoculated bladders had no discernible staining that controlled the expression of lacZ reporter gene fused in-frame at the 5′ -end to a nuclear localization sequence (NLS)46–48. (B) NF-κ B-RE/NLS-lacZ transgenic mice were transurethrally administered with PBS (a) or that containing T1F-UPEC strain UTI89 (108 cfu) (b)
Using mouse models of ascending urinary tract infection, we provide multiple lines of evidence demonstrating that (i) type 1-fimbriated uropathogenic E. coli (T1F-UPEC) triggers the trans-activation of NF-κ B-responsive elements in transgenic reporter mice (Fig. 1A–C); (ii) T1F-UPEC induces rapid nuclear translocation of the canonical NF-κ B component RelA, without affecting the non-canonical NF-κ B components, in urothelial cells of the wild-type mice (Fig. 1D; Supplemental Fig. 1); (iii) the nuclear fraction of NF-κ B from UPEC-challenged urothelial cells binds to NF-κ B-responsive DNA and trans-activates pro-inflammatory cytokine TNF-α, IL1α and IL1β genes (Supplemental Fig. 2); and (iv) the NF-κ B activation in urothelial cells is highly reproducible with divergent clinical strains of T1F-UPEC but not with non-type 1-fimbriated laboratory controls (Fig. 2A)
Summary
Responses in this pathway in genetically engineered mice lacking key NF-κ B pathway components can result in persistent inflammatory or infectious states[8]. Despite the notable progress in chronicling the lifecycle of T1F-UPEC inside the urothelium, the positive role or the dispensability of NF-κ B in countering the invading bacteria and how this might affect the pathogenesis of urinary tract infection remain unclear This is in part due to the fact that previous reports primarily employed cell lines derived from advanced human bladder cancers (e.g., T24, 5637, etc.)[31,32,33,34]. Incubation of these cell lines with lipopolysaccharide (LPS) or UPEC strains triggered nuclear translocation of NF-κ B and increased production of inflammatory cytokines, suggesting that NF-κ B is activated by UPEC32,35,36 It could be argued, that like many other cancer types the NF-κ B pathway is constitutively over-activated in bladder cancer cells[37,38], representing a heightened activation state that may not reflect how NF-κ B acts in normal urothelial cells. Our data underscore the critical importance of the activation status of urothelial NF-κ B in affecting the disease course and clinical manifestation of microbe-related urinary tract conditions including acute cystitis, recurrent bladder infections, pyelonephritis, asymptomatic bacteriuria and normal microbiome of the healthy urinary tract
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