Monocytes heterozygous for the Asp299Gly and Thr399Ile mutations in the Toll-like receptor 4 gene show no deficit in lipopolysaccharide signalling.
Toll-like receptor 4 (TLR4)-mediated recognition of lipopolysaccharide (LPS) is required for efficient recognition of Gram-negative bacterial infections. Two commonly occurring mutations in the human TLR4 gene (Asp299Gly and Thr399Ile) have recently been shown to be associated with blunted physiological responses to inhaled LPS, and with increased risk of Gram-negative bacteraemia in sepsis patients and reduced risk of atherosclerosis in an Italian population. Here we show that monocytes from individuals heterozygous for both mutations in the TLR4 gene exhibit no deficit in recognition of LPS of Escherichia coli, Neisseria meningitidis, Bacteroides fragilis, Yersinia pestis, Chlamydia trachomatis, Porphyromonas gingivalis, or Pseudomonas aeruginosa. We propose that the relatively high frequency of these mutations in the Caucasian population may reflect modified responses of carriers to alternative TLR4 agonists.
Erridge
Clett
C
Department of Medical Microbiology, University of Edinburgh Medical School, Edinburgh, EH8 9AG Scotland, UK.
Stewart
John
J
Poxton
Ian R
IR
D001224:Aspartic Acid / Q000378:metabolism*; D006090:Gram-Negative Bacteria / Q000276:immunology; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D009000:Monocytes / Q000502:physiology*; D009154:Mutation; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013912:Threonine / Q000378:metabolism*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D007375:Interleukin-1; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D013912:Threonine; D001224:Aspartic Acid