Novel mechanism of P-fimbriated Escherichia coli virulence in pyelonephritis.

U rinary tract infections (UTI) are among the most frequently encountered community-acquired or nosocomial infections. The disease burden of UTI is estimated to be 150 million cases annually worldwide (1). Catheterassociated UTI is the most frequent source of Gram-negative sepsis in hospitalized patients (2). The spectrum of disease in UTI includes cystitis, pyelonephritis, urosepsis, catheter-related infections, as well as asymptomatic bacteriuria, which requires medical management among certain, more vulnerable hosts. A conservative estimate is that 250,000 cases of pyelonephritis occur annually in the United States, many of which require hospitalization (3). Pregnancy confers an increased risk of pyelonephritis, and UTI is associated with adverse obstetrical and newborn outcomes. Patients with diabetes are also at increased risk of pyelonephritis (4). Escherichia coli is the most common cause of UTI among virtually every patient group and accounts for 80 to 90% of cases of uncomplicated pyelonephritis and cystitis among otherwise healthy women (5). E. coli that cause UTI and other uropathogens are distinguished from related members of their genus and species by the presence of specific virulence determinants, microbial adaptations promoting success in the urinary tract (6). Virulence determinants allow uropathogens to overcome intrinsic urinary tract defense mechanisms that normally protect the host against UTI, such as the flow of urine, variable pH and osmolality, lack of nutrients, exfoliation of epithelial cells, and the production of cytokines that result in recruitment of polymorphonuclear leukocytes to the bladder mucosa (6–8). Other clinical factors influence the risk of UTI in a given host, such as acquired and intrinsic differences in host susceptibility, genetic factors, and behavioral exposures. However, numerous epidemiologic, animal, and in vitro studies have indicated that virulence determinants of uropathogenic bacteria enhance fitness of these organisms for entering the urinary tract and establishing disease, particularly among otherwise healthy hosts. The virulence determinants of uropathogenic E. coli (UPEC) have been most extensively studied. These include adhesins, such as P, type 1, S, Dr, and F1C fimbriae; toxins and cytolysins, such as cytotoxic necrotizing factor, secreted autotransporter toxin, cytolethal distending toxin, and hemolysin; iron acquisition mechanisms, including aerobactin, enterobactin, and yersiniabactin; and surface components such as capsule, flagellum and lipopolysaccharide (LPS) (6–8). Adhesins are particularly important virulence determinants because the initial event in the pathogenesis of UTI is the adherence of E. coli to the urogenital mucosa by infecting E. coli, an event mediated by adhesins. Many urovirulence traits, including P fimbriae, are encoded in mobile genetic elements known as pathogenicity islands. P fimbriae appear to be especially important in E. coli pyelonephritis. Epidemiologic studies in adults and children over many years in diverse geographic locations have consistently demonstrated that these adhesins are present in nearly 100% of strains causing pyelonephritis (6,9,10). In a monkey model, P fimbriae are required for the establishment of pyelonephritis and provide a competitive edge for organisms inoculated into the bladder (11,12). In human experiments, P fimbriae enhanced the early establishment of bacteriuria (13). Each adhesin of UPEC recognizes specific cognate receptor(s) on the surface of the uroepithelium. P-fimbriated organisms bind to a minimal binding site contained in the globoseries glycosphingolipids (GSL) (14–17). Globoseries GSL are especially abundant in the human kidney and their expression is genetically determined, in parallel with the expression of ABH histo-blood group antigens (18–20). Thus, some cognate host receptors for adhesins are associated with tissue specificity and/or intrinsic differences in host susceptibility. Recent studies of several UPEC adhesins have demonstrated that fimbrial interactions with epithelial cells have further consequences, beyond conferring specificity and functioning as anchors against removal through bulk flow of urine. For example, in a mouse model of UTI, type 1 fimbriae mediate invasion of uroepithelial cells and persistence in the bladder (21). The binding of P fimbriae to uroepithelium results in a ceramide signaling and a mucosal inflammatory response via a Toll-like receptor-4 (TLR4)–dependent pathway (22–25). In this issue of JASN, Rice and colleagues (26) present a carefully designed study showing an entirely new function for P fimbriae: Impairing the local host immune response in a mouse model of pyelonephritis. The polymeric Ig receptor (pIgR) is produced by the renal epithelium and transports IgA into the urinary space. Published online ahead of print. Publication date available at www.jasn.org.