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Background  Polymorphisms affecting Toll-like receptor (TLR) structure appear to be rare, as would be expected due to their essential coordinator role in innate immunity. Here, we assess variation in TLR4 expression, rather than structure, as a mechanism to diversify innate immune responses.    Methodology/Principal Findings  We sequenced the  TLR4  promoter (4,3 kb) in Swedish blood donors. Since TLR4 plays a vital role in susceptibility to urinary tract infection (UTI), promoter sequences were obtained from children with mild or severe disease. We performed a case-control study of pediatric patients with asymptomatic bacteriuria (ABU) or those prone to recurrent acute pyelonephritis (APN). Promoter activity of the single SNPs or multiple allelic changes corresponding to the genotype patterns (GPs) was tested. We then conducted a replication study in an independent cohort of adult patients with a history of childhood APN. Last,  in vivo  effects of the different GPs were examined after therapeutic intravesical inoculation of 19 patients with  Escherichia coli  83972. We identified in total eight  TLR4  promoter sequence variants in the Swedish control population, forming 19 haplotypes and 29 genotype patterns, some with effects on promoter activity. Compared to symptomatic patients and healthy controls, ABU patients had fewer genotype patterns, and their promoter sequence variants reduced TLR4 expression in response to infection. The ABU associated GPs also reduced innate immune responses in patients who were subjected to therapeutic urinary  E. coli  tract inoculation.    Conclusions  The results suggest that genetic variation in the  TLR4  promoter may be an essential, largely overlooked mechanism to influence TLR4 expression and UTI susceptibility.

Toll-Like Receptor 4 Promoter Polymorphisms: Common TLR4 Variants May Protect against Severe Urinary Tract Infection