Terra incognito: the ureter in urinary tract infection.

Knowledge characterizing the cause and evolution of acute uncomplicated urinary infection has greatly expanded [1]. Women and girls who experience this syndrome have a familial propensity for infection that is determined, at least in part, by a modified innate immune response caused by genetic variation [2]. This propensity influences not only when infection occurs, but also clinical presentations such as whether infection is symptomatic or asymptomatic, or presents as pyelonephritis rather than being limited to the bladder. For instance, selected polymorphisms that reduce Tolllike receptor-4 function are associated with asymptomatic bacteriuria [2, 3], and genotypic variants of 1RF3, a transcription factor, and CXCR1, an IL-8 receptor, are associated with an increased familial incidence of pyelonephritis [2, 4]. Selected behavioral factors, particularly sexual intercourse or spermicide use in young, sexually active women, also increase the frequency of infection in women at risk. Infection is also contingent upon the complex interaction of virulence characteristics of Escherichia coli and the host innate immune response. E. coli are isolated from 80%–95% of episodes of acute uncomplicated urinary tract infection, and these strains comprise a subset of E. coli referred to as uropathogenic E. coli (UPEC). UPEC strains are characterized by an array of virulence factors that influence the persistence and localization of bacteria in the urinary tract, as well as the intensity of the immune response [5]. These virulence factors include fimbriae, flagella, diverse other adhesins, siderophores, toxins, polysaccharide capsules, and additional properties that facilitate the avoidance of host defenses, injury of host cells, or stimulation of the inflammatory response. A mannose-sensitive type I pilus adhesin, FimH, is universal in UPEC strains and essential for cystitis to be established [5]. In pyelonephritis, a class II PapG mannose-resistant adhesin of the P fimbrial family is associated with 80% or more of pyelonephritis strains, but is uncommon in strains from infections presenting as asymptomatic bacteriuria or acute cystitis [5, 6]. Absent from this crowded landscape is the ureter. Investigations that characterize the pathogenesis of uncomplicated urinary infection present the kidney and bladder largely in isolation, whereas they are clearly an anatomic and physiologic continuum linked by the ureter. There is no syndrome of ureteritis, and this clinical silence may partially explain the apparent neglect of the ureter in studies of urinary infection. For many patients with complicated urinary tract infection, likely including pregnant women, the progress of organisms from the bladder to the kidney seems a straightforward mechanical event when reflux of urine from the bladder into the ureter accompanies the genitourinary abnormality. But reflux is not characteristic of acute uncomplicated urinary tract infection, where the genitourinary tract is normal by definition. The ureter in this syndrome cannot simply function as an inert hollow tube, but must be permissive for bacteria to ascend from the bladder to the kidneys so that pyelonephritis develops. Progression to pyelonephritis is very infrequent in women who present with acute cystitis, so the ureter must, in most cases, maintain an effective barrier. What mechanisms allow bacteria and infection to subvert ureteric defenses and permit bacteria to reach the kidney? In this issue of The Journal, Floyd et al [7] report a series of investigations characterizing the impact of E. coli on ureteric contractility. Ureteric peristalsis is an important function for limiting bacterial ascent. A diverse library of well characterized E. coli strains were assayed in an ex vivo female rat ureter model. The E. coli strains included several UPEC originating from distinct, clinically important clonal groups, an avian pathogenic E. coli, enteropathogenic E. coli, and non-UPEC commensal strains. The participation of 1 important virulence factor, FimH, in mediating contractility Received 27 July 2012; accepted 17 August 2012; electronically published 21 September 2012. Correspondence: Lindsay E. Nicolle, MD, FRCPC, Professor, Department of Internal Medicine and Medical Microbiology, University of Manitoba, Health Sciences Centre, Room GG443 – 820 Sherbrook Street, Winnipeg, MB R3A 1R9, CANADA (lnicolle@hsc.mb.ca). The Journal of Infectious Diseases 2012;206:1494–6 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/infdis/jis558