Low CXCR1 Expression and Susceptibility to Acute Pyelonephritis

Abstract: Urinary tract infections (UTIs) are clustered in certain individuals but the molecular basis of disease susceptibility is not known. A single gene was shown to control the susceptibility to acute pyelonephritis and renal scarring in mice. The IL-8 receptor homologue (mIL-8Rh) controls neutrophil function during acute infection and the mIL-8Rh deletion causes tissue damage through neutrophil entrapment in the kidneys. To investigate if analogous defects might explain the susceptibility to urinary tract infection (UTI) in man, we examined the CXCR1 expression, mRNA levels and DNA sequences between children with acute pyelonephritis (APN) and pediatric controls. APN-prone children expressed less CXCR1 protein and mRNA than the pediatric controls (p<0.0001). DNA sequencing revealed two heterozygous CXCR1 polymorphisms (SNPs) and three mutations (variant 3-5) in the patients (38%) but only one pediatric control had an SNP (4%). The increased SNP frequency was confirmed in APN-prone adults (24% for SNP1, p<0.02 and 26% for SNP2, p<0.006). The polymorphic sequences were located in highly conserved regions of CXCR1, which potentially influenced gene expression through changes in transcription factor specificity or transcript processing. SNP1 was shown to reduce the affinity for the transcription factor RUNX1 and variant 5 close to the 3´polyadenylation site decreased the amount of large CXCR1 transcript. The CXCR1 variants may thus render individuals APN-prone by lowering CXCR1 expression, neutrophil function and the innate host defense against APN. By using a family study approach, we found that APN was more common among relatives of the APN-prone children (20/130, 15%) than controls (3/101, 3%, p < 0·002). In addition, the CXCR1 expression was low in 80 % of the APN-prone relatives, compared to adult controls (p < 0·005). The results show that genetic factors influence the susceptibility to APN and suggest that low CXCR1 expression might predispose to disease.