Toll-like Receptor Signaling and Chemokine Receptor Expression Influence the Severity of Urinary Tract Infection

Urinary tract infections (UTIs) vary in pathogenesis and severity. After their ascent into the urinary tract, bacteria may establish asymptomatic bacteriuria (ABU), cause acute cystitis, or cause acute pyelonephritis. Research during the last few decades has established that the site of infection and the disease severity are influenced by bacterial virulence. In the 1940s, hemolysin was shown to identify Escherichia coli that cause extraintestinal infections [1]. “Uropathogenic” E. coli strains were later shown to belong to a restricted set of serotypes or clones [2], and acute pyelonephritis and ABU strains were shown to differ in surface antigen repertoire [3]. Studies in the 1970s started to involve host cell interactions with attachment to the urinary tract mucosa [4]. We proposed that the disease severity was a direct result of bacterial virulence and that tissue attachment is a first critical step. The special virulence of the uropathogenic clones has subsequently been shown to include numerous virulence factors encoded on the pathogenicity islands (see Middendorf et al., this issue). The variation in urinary tract virulence reflects the ability of bacteria to trigger mucosal and systemic host responses. Through different molecular interactions, bacteria may trigger epithelial cell responses, cause cell detachment, and invade or kill cells by apoptosis (for review see [5]). Inflammation has received special attention because it determines the severity of UTI and the clearance of infection [6] (also see Agace et al. in [5]). We have studied how the inflammatory response is initiated and how it determines the resistance to UTI. Herein we argue that individuals differ in the ability to respond to UTI. We propose that pyelonephritis occurs more readily in “high responders” and that their abnormalities exaggerate the damaging rather than the protective aspects of inflammation. The “low responders,” on the other hand, have suppressed inflammatory signals, allowing bacteriuria to establish without harm