Toll-like receptor 4 promoter polymorphisms: common TLR4 variants may protect against severe urinary tract infection.
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.
Ragnarsdóttir
Bryndís
B
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine Lund, Lund University, Lund, Sweden.
Jönsson
Klas
K
Urbano
Alexander
A
Grönberg-Hernandez
Jenny
J
Lutay
Nataliya
N
Tammi
Martti
M
Gustafsson
Mattias
M
Lundstedt
Ann-Charlotte
AC
Leijonhufvud
Irene
I
Karpman
Diana
D
Wullt
Björn
B
Truedsson
Lennart
L
Jodal
Ulf
U
Andersson
Björn
B
Svanborg
Catharina
C
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
C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4