Pathogenesis

Uropathogenic E. coli first become established at a site outside the urinary tract (the large intestine, the introital or preputial areas). Colonization at these sites is influenced by adherence through P and type 1 fimbriae and by the receptor repertoire of the host. The uropathogenic clones enter the urinary tract and establish bacteriuria via the ascending route. The bacterial properties that determine this initial establishment are still poorly understood. The bacteria resist elimination with the urine flow at voiding and the killing by bacteriocins in the mucosa.

Acute pyelonephritis is caused by bacteria that reach the kidney and trigger local and systemic inflammation. The bacteria activate cells at the site of infection to secrete cytokines and other proinflammatory mediators. The molecular mechanisms through which uropathogenic bacteria elicit cytokine responses have been studied in vitro. Attachment to uroepithelial cell receptors activates transmembrane signaling events that upregulatc cvtokine mRNA

Fimbriae LPS

Hemolysin

IL-8 pyuria (neutrophil chemoattractant)

Fimbriae LPS

Hemolysin

IL-8 pyuria (neutrophil chemoattractant)

Figure 1 Early events in the pathogenesis of urinary tract infection. 1: Bacteria enter the urinary tract. Persistence is determined by (a) resistance to bacteriocins and (b) adherence factors suitable for host receptors. 2: Bacteria induce the production of inflammatory mediators by the mucosa (cytokines) which trigger local and systemic inflammation. 3: Bacteria induce cell detachment and cross the epithelial barrier. 4: Phagocytic cells eliminate bacteria. 5: Bacteria reach the bloodstream and cause urosepsis. (Drawn by W Agace.)

Figure 1 Early events in the pathogenesis of urinary tract infection. 1: Bacteria enter the urinary tract. Persistence is determined by (a) resistance to bacteriocins and (b) adherence factors suitable for host receptors. 2: Bacteria induce the production of inflammatory mediators by the mucosa (cytokines) which trigger local and systemic inflammation. 3: Bacteria induce cell detachment and cross the epithelial barrier. 4: Phagocytic cells eliminate bacteria. 5: Bacteria reach the bloodstream and cause urosepsis. (Drawn by W Agace.)

levels and protein synthesis, and results in cytokine secretion. The transmembrane signaling pathway is influenced by the fimbrial receptor specificity.

The release of cytokines and other inflammatory mediators elicits the chain of events that leads to the classical inflammatory changes associated with acute pyelonephritis (fever, elevated acute phase responses, local inflammation and loss of tubular function). The rapid influx of neutrophils (PMNs) into the urine is partly explained by the local production of interleukin 8 (IL-8), a neutrophil chemoattractant. In response to mucosal IL-8, PMNs from the circulation migrate to the epithelium, and cross the epithelial barrier into the urine. This process is also influenced by epithelial cell adhesion molecules such as ICAM-1 that are upregulated by the presence of bacteria, and bind the CDllb/CD18 neutrophil ligands. The febrile response to UTI and elevation of circulating acute phase rcactants like C reactive protein may be explained by the release of IL-6 from the site of infection. Further studies are required to define the in vivo relevance of the cytokines as mediators of disease.

In about 30% of patients with acute pyelonephritis bacteria reach the bloodstream and cause urosepsis. This involves the disruption of the epithelial barrier and survival of bacteria in the bloodstream. P Fimbriated E. coli are more common in urosepsis than in acute pyelonephritis. The role of mucosal and systemic immunity or inflammation for this phase of infection is not well understood.

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