Tuberculous meningitis (TBM) results from the haematogenous dissemination of Mycobacterium tuberculosis from the lung to the brain. Dissemination is believed to occur early during infection, before the development of adaptive immunity. Toll-like receptor 2 (TLR2) mediates recognition of M. tuberculosis and initiates the innate immune response to infection. We hypothesized that polymorphisms in the TLR2 gene influence bacterial dissemination and the development of TBM. A casecontrol study was designed to test the hypothesis. Cases of bacteriologically confirmed pulmonary tuberculosis (TB) (n ¼ 183) and TBM (n ¼ 175), and cord blood controls (n ¼ 389) were enrolled in Vietnam. TLR2 genotype 597CC was associated with susceptibility to TB (odds ratio (OR) ¼ 2.22, 95% confidence interval (CI): 1.23À3.99). The association was found with meningeal rather than pulmonary TB (TBM vs control, OR ¼ 3.26, 95% CI: 1.72À6.18), and was strongest when miliary TB was found on chest radiography (controls vs TBM with miliary TB, OR ¼ 5.28, 95% CI: 2.20À12.65). Furthermore, the association increased with the severity of neurologic symptoms (grade I TBM, OR ¼ 1.93, 95% CI: 0.54À6.92; grade II, OR ¼ 3.32, 95% CI: 0.84À13.2; and grade III, OR ¼ 5.70, 95% CI: 1.81À18.0). These results demonstrate a strong association of TLR2 SNP T597C with the development of TBM and miliary TB and indicate that TLR2 influences the dissemination of M. tuberculosis.

The MR1 antigen-presenting system is conserved among mammals and enables T cells to recognize small molecules produced by bacterial pathogens, including Mycobacterium tuberculosis (M.tb). However, it is not known if MR1-mediated antigen presentation is important for protective immunity against mycobacterial disease. We hypothesized that genetic control of MR1 expression correlates with clinical outcomes of tuberculosis infection. We performed an MR1 candidate gene association study and identified an intronic SNP (rs1052632) that was significantly associated with susceptibility to tuberculosis in a discovery and validation cohort of Vietnamese adults with tuberculosis. Stratification by site of disease revealed that rs1052632 genotype GG was strongly associated with the development of meningeal tuberculosis (OR=2.99; 95%CI 1.64-5.43; p=0.00006). Among patients with meningeal disease, absence of the G allele was associated with an increased risk of death (HR=3.86; 95%CI 1.49-9.98; p=0.005). Variant annotation tools using public databases indicate that rs1052632 is strongly associated with MR1 gene expression in lymphoblastoid cells (p=0.004) and is located within a transcriptional enhancer in epithelial keratinocytes. These data support a role for MR1 in the pathogenesis of human tuberculosis by revealing that rs1052632 is associated with MR1 gene expression and susceptibility to tuberculosis in Vietnam.

Macrophage receptor with collagenous structure (MARCO) has an important role in the phagocytosis of Mycobacterium tuberculosis (M. tuberculosis). We hypothesized that MARCO polymorphisms are associated with phagocytosis, tuberculosis (TB) disease susceptibility and presentation, and infecting lineage. We used a human cellular model to examine how MARCO genotype mediates the immune response; a case–control study to investigate tuberculosis host genetic susceptibility; and a host–pathogen genetic analysis to study host–pathogen interactions. Two MARCO heterozygous (AG) genotypes (single-nucleotide polymorphisms rs2278589 and rs6751745) were associated with impaired phagocytosis of M. tuberculosis trehalose 6,6'-dimycolate-cord factor and β-glucan-coated beads in macrophages. The heterozygous genotypes of rs2278589 and rs6751745 were also associated with increased risk of pulmonary TB (PTB; rs2278589, P=0.001, odds ratio (OR)=1.6; rs6751745, P=0.009, OR=1.4), and with severe chest X-ray abnormalities (P=0.007, OR=1.6). These two genotypes were also associated with the Beijing lineage (rs2278589, P=0.001, OR=1.7; rs6751745, P=0.01, OR=1.5). Together, these results suggest that MARCO polymorphisms may regulate phagocytosis of M. tuberculosis and susceptibility and severity of PTB. They also suggest MARCO genotype and Beijing strains may interact to increase the risk of PTB.

CD1 proteins are antigen-presenting molecules that evolved to present lipids rather than peptides to T cells. However, unlike major histocompatibility complex genes, CD1 genes show low rates of polymorphism and have not been clearly associated with human disease. We report that an intronic polymorphism in CD1A (rs411089) is associated with susceptibility to tuberculosis in two cohorts of Vietnamese adults (combined cohort odds ratio 1.78; 95%CI: 1.24-2.57; p=0.001). These data strengthen the hypothesis that CD1A-mediated lipid antigen presentation is important for controlling tuberculosis in humans.