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

A H Montes1, Victor Asensi, Victoria Alvarez

  • 1Department of Biochemistry and Molecular Biology, Oviedo University Medical School and Hospital Central de Asturias, Oviedo, Spain.

Clinical and Experimental Immunology
|February 21, 2006
PubMed

Insights

The Toll-like receptor 4 (TLR4) Asp299Gly polymorphism is linked to increased susceptibility to Gram-negative and chronic osteomyelitis. This genetic variation impacts neutrophil function, potentially affecting infection outcomes.

Area of Science:

  • Immunogenetics
  • Infectious Diseases
  • Molecular Biology

Background:

  • Osteomyelitis is a bone infection often caused by Staphylococcus aureus or Gram-negative bacteria.
  • Toll-like receptors (TLRs) play a crucial role in the innate immune response by recognizing microbial products and activating signaling pathways like NF-kappaB.
  • Genetic variations in TLRs, such as polymorphisms in TLR2 and TLR4, have been associated with susceptibility to bacterial infections.

Purpose of the Study:

  • To investigate the association between specific TLR2 and TLR4 gene polymorphisms and osteomyelitis in patients.
  • To determine if these polymorphisms influence susceptibility to Gram-negative bacteria, hematogenous spread, or chronic forms of osteomyelitis.
  • To analyze the functional consequences of the TLR4 Asp299Gly polymorphism on neutrophil responses.

Main Methods:

  • Genotyping of TLR2 (Arg753Gln) and TLR4 (Asp299Gly, Thr399Ile) polymorphisms in 80 osteomyelitis patients and 155 healthy controls.
  • Statistical analysis to compare genotype frequencies between patients and controls.
  • Functional assays on neutrophils from patients homozygous for the TLR4 Asp299Gly polymorphism, assessing lipopolysaccharide (LPS)-induced apoptosis, NF-kappaB inhibitor phosphorylation, and cytokine levels (IL-6, TNF-alpha).

Main Results:

  • Homozygosity for the TLR4 Asp299Gly polymorphism was significantly more frequent in osteomyelitis patients (3.8%) compared to controls (0%, P = 0.038).
  • Carriers of the TLR4 Asp299Gly allele were more likely to have Gram-negative, hematogenous, and/or chronic osteomyelitis (P < 0.031).
  • Neutrophils from TLR4 Asp299Gly homozygous patients exhibited reduced LPS-induced apoptosis reduction and lower levels of IL-6 and TNF-alpha.

Conclusions:

  • The TLR4 Asp299Gly polymorphism is associated with an increased risk of developing Gram-negative and hematogenous osteomyelitis.
  • This genetic variation may influence disease progression and severity by altering innate immune cell function.
  • No association was found between the TLR2 Arg753Gln polymorphism and osteomyelitis in this cohort.

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