Role of Neutrophils and Innate Immune Mechanisms in Urinary Tract Infections

Abstract: Urinary tract infections (UTI) are among the most common infections in man. Despite their prevalence, information on the molecular mechanisms defects that explain the increased susceptibility to disease are lacking. This study focused on mucosal inflammation and the molecular mechanisms by which uropathogenic Escherichia coli activate this response. P fimbriae are expressed by most E. coli strains that cause acute pyelonephritis. By binding to Gala1-4Galb containing motifs in the globoseries of glycosphingolipids P fimbriae trigger inflammatory responses that underlie disease pathology. P fimbriae were shown here to utilize the Toll-like receptor 4 (TLR4) pathway to activate inflammation. P fimbriated E. coli induced a strong inflammatory response in TLR4+ mice, but not in TLR4- mice. In contrast to previously described activation of TLR4, the P fimbriae induced signal was independent of the LPS/LBP/CD14 pathway. The TLR4 deficiency was shown to impair resistance to UTI through an effect on neutrophil recruitment. Uropathogenic E. coli induced a rapid and strong neutrophil recruitment in TLR4+ mice, but only a weak response in TLR4- mice. TLR4+ mice cleared infection, while in TLR4- mice bacterial numbers increased with time. Neutrophil depletion converted the TLR4+ mice to the TLR4- susceptible phenotype. Neutrophil recruitment was shown to depend on IL-8 and IL-8 receptors. In vitro neutrophil transepithelial migration was blocked by antibodies to the interleukin-8 receptor CXCR1, and neutrophils of IL-8R knockout mice failed to cross the urinary tract epithelium and accumulated in subepithelial tissue compartments. mIL-8Rh knock-out mice failed to clear infection, developed symptoms of disease, and showed evidence of renal scarring. Subsequent studies showed that children prone to acute pyelonephritis have decreased neutrophil CXCR1 expression. The results suggest that TLR and CXCR expression determine neutrophil recruitment to the infected urinary tract, and suggest that a CXCR1 deficiency might underlie increased susceptibility to acute pyelonephritis.