Urinary Tract Infection: Pathogenesis and Outlook

Mouse and human studies have revealed that during acute cystitis Escherichia coli and other Gram-negative uropathogens can occupy the cytoplasm of bladder epithelial cells, using this niche as a haven for replication while protected from infiltrating neutrophils. Novel therapeutics for urinary tract infection (UTI) are being explored, based on detailed molecular and structural information on bacterial virulence factor expression as well as patterns of bacterial binding to the urinary epithelium, iron acquisition, and other pathogenic processes. Highly expressed and immunogenic bacterial factors, including siderophores, have been identified in rodent models, potentially informing the development of vaccines and immunotherapies for UTI. However, the putative role of adaptive immunity in the control of lower-tract UTI remains unclear. Although the urinary tract is traditionally considered to be sterile, advances in metagenomics and other technologies have enabled the first definitions of a ‘urinary microbiome’, which may alter the way in which we think about UTI (e.g., as a dysbiosis rather than simply the introduction of one pathogenic species). Technical advances in mouse models now permit detailed modeling of complicated UTI syndromes common in humans – recurrent UTI, catheter-associated UTI, UTI in the male host, and ascending renal abscess formation. The clinical syndromes comprising urinary tract infection (UTI) continue to exert significant impact on millions of patients worldwide, most of whom are otherwise healthy women. Antibiotic therapy for acute cystitis does not prevent recurrences, which plague up to one fourth of women after an initial UTI. Rising antimicrobial resistance among uropathogenic bacteria further complicates therapeutic decisions, necessitating new approaches based on fundamental biological investigation. In this review, we highlight contemporary advances in the field of UTI pathogenesis and how these might inform both our clinical perspective and future scientific priorities. The clinical syndromes comprising urinary tract infection (UTI) continue to exert significant impact on millions of patients worldwide, most of whom are otherwise healthy women. Antibiotic therapy for acute cystitis does not prevent recurrences, which plague up to one fourth of women after an initial UTI. Rising antimicrobial resistance among uropathogenic bacteria further complicates therapeutic decisions, necessitating new approaches based on fundamental biological investigation. In this review, we highlight contemporary advances in the field of UTI pathogenesis and how these might inform both our clinical perspective and future scientific priorities. a class of antimicrobial peptides; there is a single cathelicidin encoded in the human and mouse genomes. a broadly conserved molecular paradigm for Gram-negative bacterial secretion of polymeric surface structures, including pili. a mammalian enzyme expressed in many cell types that promotes the generation of immunostimulatory molecules including prostaglandins. bacterial infection of the urinary bladder. a secreted UPEC toxin that causes cell death to neutrophils and other leukocytes. a broad class of antimicrobial peptides some of which are also secreted in the urinary tract, especially during infection. shedding of the superficial epithelial layer of the bladder. whip-like surface structures produced by many UPEC that propel the organism in swimming motility. a large subset of bacteria, including pathogenic and nonpathogenic species, possessing an outer membrane and periplasmic space outside the cell membrane; so called because they do not retain the purple crystal violet during the Gram-staining procedure. a multifunctional secreted toxin of UPEC and other pathogenic bacteria. biofilm-like collections of UPEC residing within superficial epithelial cells of the bladder. a small molecule derived from mannose that serves as a high-affinity ligand for FimH, the adhesive subunit of type 1 pili. an ecological community of commensal, symbiotic, and pathogenic organisms occupying a body space. a major transcriptional pathway regulating inflammation and apoptosis, stimulated by activation of TLRs and other host cell sensors. a small molecule designed to interrupt the function of the chaperone promoting pilus assembly. heteropolymeric surface structures expressed by some UPEC strains and associated with adherence to the kidney epithelium in some hosts. bacterial infection of the kidney. chronically resident UPEC that persists in bladder tissue following resolution of acute cystitis and may represent a seed for recurrent cystitis. a large collection of neutrophilic pus surrounding a nidus of bacterial infection in the kidney parenchyma. a bacterial protein with high affinity for iron; secreted from bacteria and re-internalized once it captures iron from the host. hair-like, adhesive, heteropolymeric surface structures expressed by UPEC that mediate binding to the bladder epithelium. a specialized, multicomponent protein complex assembled by certain pathogenic Gram-negative bacteria (e.g., Salmonella) to accomplish the delivery of effector proteins directly into host cells. comprise cystitis, pyelonephritis, renal abscess, urethritis, and prostatitis. the most common bacterial cause of UTI. mannosylated proteins decorating the apical surfaces of superficial bladder epithelial cells; provide a permeability barrier but also offer binding sites for UPEC and other uropathogens. movement of urine in a retrograde direction from the bladder to the renal pelvis and collecting system.