Toll-like receptor 4 region genetic variants are associated with susceptibility to melioidosis
T E West1, W Chierakul, N Chantratita
1Division of Pulmonary & Critical Care Medicine, Department of Medicine, Harborview Medical Center, University of Washington, Seattle, WA 98104, USA. tewest@u.washington.edu
Abstract:
Melioidosis is a tropical infection caused by the Gram-negative soil saprophyte Burkholderia pseudomallei. Despite broad exposure of northeastern Thais, disease develops in only a small proportion of individuals. Although diabetes is a risk factor, the mechanisms of host susceptibility to melioidosis are still poorly understood. We postulated that Toll-like receptors (TLRs) regulate host susceptibility to disease, and that genetic variation in TLRs is associated with melioidosis. We analyzed the frequency of eight previously described TLR pathway polymorphisms in 490 cases compared with 950 non-hospitalized controls or 458 hospitalized controls. Based on these results, we then analyzed the frequency of additional TLR4 or TLR6-1-10 region polymorphisms in cases and controls. We found that the TLR4(1196C>T) variant was associated with protection from melioidosis when compared with non-hospitalized controls. The TLR1(742A>G) and TLR1(-7202A>G) variants were associated with melioidosis when compared with hospitalized controls. In further analyses, we found that two additional TLR4 region polymorphisms were associated with disease. In diabetics, three other TLR6-1-10 region polymorphisms were associated with disease when compared with hospitalized controls. We conclude that TLR genetic variants may modulate host susceptibility to melioidosis. Confirmation of these findings and further investigation of the mechanisms are required.
Insights
Genetic variations in Toll-like receptors (TLRs) may influence susceptibility to melioidosis, a tropical bacterial infection. Certain TLR4 and TLR1 gene variants were linked to protection or increased risk of developing the disease.
Area of Science:
- Immunology
- Genetics
- Infectious Diseases
Background:
- Melioidosis, caused by Burkholderia pseudomallei, is prevalent in tropical regions like northeastern Thailand.
- Host susceptibility mechanisms for melioidosis remain poorly understood, despite diabetes being a known risk factor.
Purpose of the Study:
- To investigate the association between genetic variations in Toll-like receptors (TLRs) and host susceptibility to melioidosis.
- To identify specific TLR polymorphisms that correlate with disease development or protection.
Main Methods:
- Case-control study comparing frequencies of TLR pathway polymorphisms in melioidosis cases and controls (non-hospitalized and hospitalized).
- Analysis included eight known TLR polymorphisms, followed by investigation of additional TLR4 and TLR6-1-10 region variants.
Main Results:
- The TLR4(1196C>T) variant showed a protective association against melioidosis compared to non-hospitalized controls.
- TLR1(742A>G) and TLR1(-7202A>G) variants were associated with increased melioidosis risk compared to hospitalized controls.
- Additional TLR4 and TLR6-1-10 region polymorphisms were linked to disease, particularly in diabetic patients.
Conclusions:
- Genetic variants in Toll-like receptors may play a role in modulating host susceptibility to melioidosis.
- Further research is needed to confirm these findings and elucidate the underlying mechanisms.
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