Subversion of Host Innate Immunity by Uropathogenic Escherichia coli

Abstract

Uropathogenic Escherichia coli (UPEC) cause the majority of community-onset urinary tract infections (UTI) and represent a major etiologic agent of healthcare-associated UTI. Introduction of UPEC into the mammalian urinary tract evokes a well-described inflammatory response, comprising pro-inflammatory cytokines and chemokines as well as cellular elements (neutrophils and macrophages). In human UTI, this inflammatory response contributes to symptomatology and provides means for diagnosis by standard clinical testing. Early in acute cystitis, as demonstrated in murine models, UPEC gains access to an intracellular niche that protects a population of replicating bacteria from arriving phagocytes. To ensure the establishment of this protected niche, UPEC employ multiple strategies to attenuate and delay the initiation of host inflammatory components, including epithelial secretion of chemoattractants. Recent work has also revealed novel mechanisms by which UPEC blunts neutrophil migration across infected uroepithelium. Taken together, these attributes distinguish UPEC from commensal and nonpathogenic E. coli strains. This review highlights the unique immune evasion and suppression strategies of this bacterial pathogen and offers directions for further study; molecular understanding of these mechanisms will inform the development of adjunctive, anti-virulence therapeutics for UTI.

Local Generation of Kynurenines Mediates Inhibition of Neutrophil Chemotaxis by Uropathogenic Escherichia coli

“…Within the mammalian bladder, UPEC employs an array of distinct strategies to attenuate the initial recruitment of PMN, providing an opportunity for the pathogen to establish residence within uroepithelial cells (41). The PMN that ultimately respond to infection specifically locate and surround these infected epithelial cells, but the replicating UPEC within are sheltered (42). We previously reported one such strategy, namely, UPEC-specific induction of local IDO1 activity (23).…”

The SPOR Domain, a Widely Conserved Peptidoglycan Binding Domain That Targets Proteins to the Site of Cell Division

“…While this phenotype clearly smacks of an artifact, according to a recent report damX is highly induced when uropathogenic E. coli is grown under conditions that mimic the bladder, resulting in the formation of filamentous cells similar to those observed in samples from people suffering from bladder infections (29). It is thought that filamentation contributes to virulence by obstructing phagocytosis and improving adherence of the bacteria to bladder cells (30). Another SPOR domain protein that has been linked to pathogenesis is MldA of Peptoclostridium difficile, the leading cause of antibiotic-associated diarrhea (31,32).…”

Urinary Tract Infection: Pathogenesis and Outlook

“…Arrival in the bladder triggers a TLR4-dependent, lipopolysaccharide (LPS)-stimulated inflammatory response from bladder epithelial cells and resident leukocytes, culminating in the activation of the NF-κB pathway , which in turn promotes the expression of inflammatory cytokines and neutrophil chemoattractants [39]. This inflammatory milieu engenders massive neutrophil influx into the bladder tissue and lumen, correlating with a diagnostic hallmark of UTI.…”

“…The formation of IBCs is a key means by which bacteria subvert neutrophil activity, as arriving neutrophils accurately locate IBC-bearing facet cells but cannot access the bacteria within [39, 54]. UPEC can subvert and delay the innate immune response in multiple ways (reviewed in [39]).…”