TLR9 gene region polymorphisms and susceptibility to tuberculosis in Vietnam

Abstract

Summary Humans exposed to Mycobacterium tuberculosis (Mtb) show variation in susceptibility to infection and differences in tuberculosis (TB) disease outcome. Toll-like receptor 9 (TLR9) is a pattern recognition receptor that mediates recognition of Mtb and modulates Mtb-specific T-cell responses. Using a case-population design, we evaluated whether single nucleotide polymorphisms (SNPs) in the TLR9 gene region are associated with susceptibility to pulmonary or meningeal TB as well as neurologic presentation and mortality in the meningeal TB group. In a discovery cohort (n = 352 cases, 382 controls), three SNPs were associated with TB (all forms, p<0.05) while three additional SNPs neared significance (0.05<p<0.1). When these six SNPs were evaluated in a validation cohort (n = 339 cases, 367 controls), one was significant (rs352142) while another neared significance (rs352143). When the cohorts were combined, rs352142 was most strongly associated with meningeal tuberculosis (dominant model; p=0.0002, OR 2.36, CI 1.43-3.87) while rs352143 was associated with pulmonary tuberculosis (recessive model; p=0.006, OR 5.3, CI 1.26-31.13). None of the SNPs were associated with mortality. This is the first demonstration of an association between a TLR9 gene region SNP and tuberculous meningitis. In addition, this extends previous findings that support associations of TLR9 SNPs with pulmonary tuberculosis.

Persistent mycobacteria evade an antibacterial program mediated by phagolysosomal TLR7/8/MyD88 in human primary macrophages

“…TLR3, 7, 8 and 9 depend on the protein Unc-93 homolog B1 (UNC93B1) to traffic from the endoplasmic reticulum to endolysosomal compartments where they detect nucleic acids [ 10 , 11 ]. TLR9 has previously been shown to recognize mycobacterial DNA [ 12 , 13 ]. TLR7 and TLR8 recognize single-stranded RNA and RNA degradation products from viruses and bacteria, and polymorphisms in TLR7 and 8 have been associated with increased susceptibility to pulmonary tuberculosis [ 11 , 14 – 22 ].…”

The pathogenesis of tuberculous meningitis

“…For instance, mutations and polymorphisms within the genes involved in the TLR pathway have been associated with susceptibility to infection in TB. A recent study of patients with TBM in Vietnam was the first to demonstrate an association between single nucleotide polymorphisms (SNPs) in the TLR9 gene region and TBM . Further, a Vietnamese study found an association between TLR2 SNP T597C and the development of TBM and miliary TB, suggesting that TLR2 influences the dissemination of M.tb .…”

Diminished TLR2-TLR9 mediated CD4+ T cell responses are associated with increased inflammation in intraocular tuberculosis

“…Like pulmonary tuberculosis 25 , 26 , variety of host factors including, genetic makeup, antigenic exposure, initial innate immune responses and the ensuing adaptive immune responses may determine the clinical outcomes in IOTB. Polymorphisms in TLR genes 27 – 30 , IL-10 26 and defective TLR9 responses have been reported to increase susceptibility to pulmonary tuberculosis 15 . However, there is lacuna in knowledge about the immune responses in pathogenesis of IOTB.…”