The Toll‐like receptor 4 (Asp299Gly) polymorphism is a risk factor for Gram‐negative and haematogenous osteomyelitis

• Published in: Clinical and experimental immunology Vol. 143; no. 3; pp. 404 - 413
• Main Authors: Montes, A. H., Asensi, Victor, Alvarez, Victoria, Valle, Eulalia, Ocaña, M. G., Meana, A., Carton, J. A., Paz, Jose, Fierer, J., Celada, A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-03-2006; Blackwell; Oxford University Press; Blackwell Science Inc
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Apoptosis - immunology; Biological and medical sciences; Cells, Cultured; Clinical Studies; Cytokines - metabolism; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genetic Predisposition to Disease; Genotype; Gram-Negative Bacterial Infections - genetics; Gram-Negative Bacterial Infections - immunology; Gram‐negative bacteria; Humans; I-kappa B Proteins - metabolism; Immunopathology; Male; Medical sciences; Middle Aged; neutrophils; Neutrophils - immunology; NF-KappaB Inhibitor alpha; osteomyelitis; Osteomyelitis - genetics; Osteomyelitis - immunology; Osteomyelitis - microbiology; Phosphorylation; Polymorphism, Genetic; polymorphisms; Risk Factors; Staphylococcus aureus; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - immunology; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; toll‐like receptors; Immunopathology; Genetic variability; Toll like receptor 4; toll-like receptors; Diseases of the osteoarticular system; Granulocyte; Genotype; Toll like receptor; Epidemiology; polymorphisms; osteomyelitis; Immunology; Osteitis; Risk factor; Neutrophil; Gram-negative bacteria; neutrophils; Gram negative bacteria; Polymorphism
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.2005.03002.x

Summary
Osteomyelitis is a bone infection caused mostly by Staphylococcus aureus but also by Gram‐negative bacteria. Toll‐like receptors (TLRs), after recognizing microbial products, induce a signal in neutrophils, leading to NF‐κB activation and transcription of pro‐inflammatory genes. Polymorphisms in TLR2 (Arg753Gln) and TLR4 (Asp299Gly, Thr399Ile) genes are associated with bacterial infections, we therefore studied these polymorphisms in osteomyelitis patients. Homozygotes for the TLR4 (Asp299Gly) polymorphism were significantly more frequent among the 80 osteomyelitis patients than in the 155 healthy controls (3/80, 3·8%versus 0/155, 0%; P = 0·038). Carriers of one or two G alleles of this tlr4 polymorphism were more likely to have Gram‐negative, haematogenous and/or chronic osteomyelitis than those without this mutation (P < 0·031). Patients with the TLR4 (Thr399Ile) mutant, which cosegregates with the TLR4 (Asp299Gly), were also carriers of this second polymorphism. No differences for the TLR2 (Arg753Gln) genotypes were found between patients and controls. Neutrophils of patients homozygous for the TLR4 (Asp299Gly) polymorphism showed lower LPS‐induced apoptosis reduction, phosphorylation of the inhibitor of NF‐κB, and lower IL‐6 and TNF‐α levels (P < 0·05). We report here for the first time an association between this TLR4 polymorphism and susceptibility to Gram‐negative bacteria and haematogenous osteomyelitis.