title: Toll-like receptor 4 promoter polymorphisms: common TLR4 variants may protect against severe urinary tract infection.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine Lund, Lund University, Lund, Sweden.
authors.forename: Bryndís
authors.initials: B
authors.lastname: Ragnarsdóttir
authors.forename: Klas
authors.initials: K
authors.lastname: Jönsson
authors.forename: Alexander
authors.initials: A
authors.lastname: Urbano
authors.forename: Jenny
authors.initials: J
authors.lastname: Grönberg-Hernandez
authors.forename: Nataliya
authors.initials: N
authors.lastname: Lutay
authors.forename: Martti
authors.initials: M
authors.lastname: Tammi
authors.forename: Mattias
authors.initials: M
authors.lastname: Gustafsson
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Lundstedt
authors.forename: Irene
authors.initials: I
authors.lastname: Leijonhufvud
authors.forename: Diana
authors.initials: D
authors.lastname: Karpman
authors.forename: Björn
authors.initials: B
authors.lastname: Wullt
authors.forename: Lennart
authors.initials: L
authors.lastname: Truedsson
authors.forename: Ulf
authors.initials: U
authors.lastname: Jodal
authors.forename: Björn
authors.initials: B
authors.lastname: Andersson
authors.forename: Catharina
authors.initials: C
authors.lastname: Svanborg
mesh_terms: D000293:Adolescent; D001437:Bacteriuria / Q000150:complications / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013548:Sweden; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D014158:Transcription, Genetic; D014552:Urinary Tract Infections / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy; D055815:Young Adult
chemical_list: C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4