title: A mucosal imprint left by prior Escherichia coli bladder infection sensitizes to recurrent disease.
abstract: Recurrent bacterial infections are a significant burden worldwide, and prior history of infection is often a significant risk factor for developing new infections. For urinary tract infection (UTI), a history of two or more episodes is an independent risk factor for acute infection. However, mechanistic knowledge of UTI pathogenesis has come almost exclusively from studies in naive mice. Here we show that, in mice, an initial Escherichia coli UTI, whether chronic or self-limiting, leaves a long-lasting molecular imprint on the bladder tissue that alters the pathophysiology of subsequent infections, affecting host susceptibility and disease outcome. In bladders of previously infected versus non-infected, antibiotic-treated mice, we found (1) an altered transcriptome and defects in cell maturation, (2) a remodelled epithelium that confers resistance to intracellular bacterial colonization, and (3) changes to cyclooxygenase-2-dependent inflammation. Furthermore, in mice with a history of chronic UTI, cyclooxygenase-2-dependent inflammation allowed a variety of clinical E. coli isolates to circumvent intracellular colonization resistance and cause severe recurrent UTI, which could be prevented by cyclooxygenase-2 inhibition or vaccination. This work provides mechanistic insight into how a history of infection can impact the risk for developing recurrent infection and has implications for the development of therapeutics for recurrent UTI.
authors: Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors: Valerie P
authors: VP
authors: O'Brien
authors: Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, St Louis, Missouri 63110, USA.|Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors: Thomas J
authors: TJ
authors: Hannan
authors: Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors: Lu
authors: L
authors: Yu
authors: The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA.
authors: Jonathan
authors: J
authors: Livny
authors: Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St Louis, Missouri 63110, USA.|Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors: Elisha D O
authors: ED
authors: Roberson
authors: Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors: Drew J
authors: DJ
authors: Schwartz
authors: Departments of Urology and Genetics &Development, Columbia University, New York, New York 10032, USA.
authors: Spenser
authors: S
authors: Souza
authors: Departments of Urology and Genetics &Development, Columbia University, New York, New York 10032, USA.
authors: Cathy L
authors: CL
authors: Mendelsohn
authors: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors: Marco
authors: M
authors: Colonna
authors: Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, St Louis, Missouri 63110, USA.|Department of Obstetrics and Gynecology, Washington University School of Medicine, St Louis 63110, Missouri, USA.
authors: Amanda L
authors: AL
authors: Lewis
authors: Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors: Scott J
authors: SJ
authors: Hultgren
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004848:Epithelium / Q000473:pathology; D004926:Escherichia coli / Q000302:isolation & purification*; D004927:Escherichia coli Infections / Q000382:microbiology* / Q000503:physiopathology*; D020869:Gene Expression Profiling; D007249:Inflammation / Q000473:pathology; D051379:Mice; D012008:Recurrence; D001743:Urinary Bladder / Q000382:microbiology*; D014552:Urinary Tract Infections / Q000382:microbiology* / Q000503:physiopathology*
chemical_list: D051546:Cyclooxygenase 2