Influence of host genetics on innate immunity and susceptibility to urinary tract infection

Abstract: It has been known for a long time that the clinical manifestations of urinary tract infections (UTI) differ markedly between individuals, ranging from a sometimes beneficial, asymptomatic state to life threatening infections. This variability in clinical manifestation can be explained in part by the arsenal of virulence factors of the bacteria but the predisposition of the patient is equally important. In this thesis we present three candidate genes, TLR4, CXCR1 and IRF3 that have major impact on UTI susceptibility by affecting the patient’s ability to cope with an invading pathogen and mount an appropriate immune response. In patients prone to acute pyelonephritis (APN) we detected increased frequency of three unique mutations and two known SNPs compared to controls. Furthermore, APN prone children expressed less CXCR1 protein than the pediatric controls and two sequence variants were shown to impair transcription. In patients with asymptomatic bacteriuria (ABU) we detected significantly lower levels of TLR4 compared to pediatric controls. We assessed if variation in TLR4 expression, rather than structure, was a mechanism to diversify innate immune responses. We identified in total eight TLR4 promoter sequence variants in the Swedish population. The promoter sequence variation was examined in children with ABU or APN and compared to APN patients and healthy controls, ABU patients had fewer haplotypes and genotype patterns, and combination of their promoter sequence variants reduced TLR4 expression in response to infection in vitro. These results are consistent with TLR4 expression levels influencing innate immunity and potentially link genetic variation in TLR4 to UTI susceptibility. Finally, we presented a previously unknown signaling pathway that is critical for distinguishing pathogens from commensals at the mucosal barrier. We show that pathogen-mediated ceramide release, from membrane sphingolipids, activates an innate immune response through TLR4, followed by TRAM phosphorylation, MAPK signaling and nuclear translocation of IRF3. Evidence that this signaling pathway is crucial for antimicrobial host defence was demonstrated in IRF3 -/- mice, in which bacterial burden, acute mortality and renal damage were dramatically augmented. Furthermore, differential IRF3 promoter sequences between children with severe, symptomatic UTI and asymptomatic carriers suggested relevance of this pathway for human disease.