Aberrant Toll-like receptor 2 promoter methylation in blood cells from patients with pulmonary tuberculosis

• Five CpG sites of the TLR2 promoter region are hyper-methylated in TB patients.
• DNA methylation level at CpG-18 is further increased in drug-resistant TB.
• Pulmonary TB patients have lower TLR2 expression on blood monocyte.
• Pulmonary TB patients have higher TLR2 expression on blood NK cell.
• CpG-18 methylation and TLR2 expressions are reversed after anti-TB treatment.

SummaryObjectivesToll-like receptor 2 (TLR2) is a major mediator of innate immunity against tuberculosis (TB). This study aimed to determine if TLR2 promoter DNA methylation is associated with pulmonary TB.MethodsThe DNA methylation levels of 20 CpG sites over the TLR2 promoter region and TLR2 gene/protein expressions of immune cells of the blood were examined in 99 sputum culture-positive pulmonary TB patients and 77 healthy subjects (HS).ResultsTB patients had higher methylation levels over five CpG sites (3, 7, 9, 13, and 18), lower TLR2 gene expression, lower TLR2 expression on monocyte, higher TLR2 expression on NK cell, and higher serum TNF-α/IFN-γ levels than HS after adjusting for confounding factors. Patients with a high bacillary load had lower methylation levels at CpG-15, -17, and -20. Patients with drug-resistant TB had higher CpG-18 methylation levels and lower TLR2 expression on NK cell. Patients with far advanced lesion on chest radiograph had higher serum TNF-α level and higher TLR2 expression on NK cell. Patients with a high TLR2 expression on NK cell had lower one-year survival. CpG-18 methylation level, TLR2 expressions on monocyte/NK cell, and TNF-α/IFN-γ levels were all reversed to normal after 6-month anti-TB treatment.ConclusionsAberrant methylation of certain CpG sites over TLR2 promoter region is associated with active pulmonary TB or its phenotypes, probably through the down-regulation of TLR2 expression.