Host Genetic Variation, Innate Immunity, and Susceptibility to Urinary Tract Infection

Abstract

Microbial determinants of acute-disease severity and tissue damage have been extensively studied, but less is known about genetic variation influencing host susceptibility. This chapter discusses two candidate genes with strong effects on the innate immune response and the antibacterial defense in the urinary tract and with major but opposite effects on urinary tract infection (UTI) susceptibility. The chapter explains that defects in TLR4 expression are protective and associated with asymptomatic bacteriuria (ABU) while defects in CXCR1 expression promote acute pyelonephritis (APN) and renal scarring. C3H/HeJ mice, then known as lipopolysaccharide (LPS)-nonresponder mice, had an increased susceptibility to UTI, as shown by delayed bacterial clearance. It also had an impaired innate immune response, suggesting that defects in innate immunity are of great importance for the antibacterial defense of the urinary tract. Studies of the murine model showed that the antibacterial defense of the urinary tract mucosa relies on innate immunity and that TLR4 plays a central role in the early host defense against infection. The results suggest that genetic variation of the TLR4 promoter is an essential, largely overlooked mechanism to influence TLR4 expression and UTI susceptibility. It was found that the protein expression was reduced and additionally the level of CXCR1 transcript and protein expression was lower in this new subset of pediatric patients. There is a great clinical need to identify genetic variants that improve resistance or increase susceptibility to infectious pathogens.