Urinary tract infections as a model for innate mucosal immunity

Most studies on innate immunity have focused on macrophages, as these cells are crucial defenders against infection of the systemic compartments. This chapter talks about (i) the molecular mechanisms used by bacteria to trigger the innate host response, (ii) neutrophils as effectors of the antimicrobial defense of the urinary tract, and (iii) genetic defects in innate host defense pathways that explain the susceptibility to urinary tract infections (UTIs). P-fimbriated Escherichia coli is used to examine the role of recognition receptors and toll-like receptor-4 (TLR4) coreceptors in epithelial cell activation. Cell activation can proceed in two steps, involving a primary ligand-binding receptor and a second receptor responsible for transmembrane signaling, which in this model is TLR4. The authors have speculated that epithelial unresponsiveness to lipopolysaccharide (LPS) may be essential to maintain mucosal integrity, and have used the murine IL-8 receptor homologue (mIL-8Rh-/-) mouse to study chemokines and chemokine receptors in the defense against UTI. Inactivation of a single gene encoding mIL-8Rh is sufficient to convert the mice from a resistant to a susceptible phenotype, as defined both by acute disease susceptibility and by chronic disease development. The chemokine receptors must be functional to avoid the trapping of neutrophils that results in tissue destruction.