title: Filamentation by Escherichia coli subverts innate defenses during urinary tract infection.
abstract: To establish disease, an infecting organism must overcome a vast array of host defenses. During cystitis, uropathogenic Escherichia coli (UPEC) subvert innate defenses by invading superficial umbrella cells and rapidly increasing in numbers to form intracellular bacterial communities (IBCs). In the late stages of the IBC pathway, filamentous and bacillary UPEC detach from the biofilm-like IBC, fluxing out of this safe haven to colonize the surrounding epithelium and initiate subsequent generations of IBCs, and eventually they establish a quiescent intracellular reservoir. Filamentous UPEC are not observed during acute infection in mice lacking functional Toll-like receptor 4 (TLR4), suggesting that the filamentous phenotype arises in response to host innate immunity. We investigated SulA, a cell division inhibitor associated with the SOS response, to gain insight into the role of filamentous UPEC in pathogenesis. A transcriptional reporter from P(sulA) revealed spatial and temporal differences in expression within IBCs, and it was active in the majority of filamentous UPEC. Although UTI89 and UTI89 DeltasulA both formed first-generation IBCs equally well, UTI89 DeltasulA was sharply attenuated in formation of second-generation IBCs and establishment of the quiescent intracellular reservoir. The virulence of UTI89 DeltasulA was restored in TLR4-deficient mice, suggesting that filamentation facilitates the transition to additional rounds of IBC formation by subverting innate immune responses. These findings demonstrate that transient SulA-mediated inhibition of cell division is essential for UPEC virulence in the murine model of cystitis.
authors.affiliation: Department of Molecular Microbiology and Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA. justices@ccri.net
authors.forename: Sheryl S
authors.initials: SS
authors.lastname: Justice
authors.forename: David A
authors.initials: DA
authors.lastname: Hunstad
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Seed
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hultgren
mesh_terms: D000818:Animals; D004926:Escherichia coli / Q000472:pathogenicity / Q000502:physiology*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D051379:Mice; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014552:Urinary Tract Infections / Q000235:genetics / Q000378:metabolism / Q000382:microbiology* / Q000517:prevention & control*; D014774:Virulence
chemical_list: D029968:Escherichia coli Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C053139:sulA protein, E coli