title: A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis.
abstract: 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 case-control study was designed to test the hypothesis. Cases of bacteriologically confirmed pulmonary tuberculosis (TB) (n=183) and TBM (n=175), and cord blood controls (n=389) were enrolled in Vietnam. TLR2 genotype 597CC was associated with susceptibility to TB (odds ratio (OR)=2.22, 95% confidence interval (CI): 1.23-3.99). The association was found with meningeal rather than pulmonary TB (TBM vs control, OR=3.26, 95% CI: 1.72-6.18), and was strongest when miliary TB was found on chest radiography (controls vs TBM with miliary TB, OR=5.28, 95% CI: 2.20-12.65). Furthermore, the association increased with the severity of neurologic symptoms (grade I TBM, OR=1.93, 95% CI: 0.54-6.92; grade II, OR=3.32, 95% CI: 0.84-13.2; and grade III, OR=5.70, 95% CI: 1.81-18.0). 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.
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: N T T
authors.initials: NT
authors.lastname: Thuong
authors.forename: T R
authors.initials: TR
authors.lastname: Hawn
authors.forename: G E
authors.initials: GE
authors.lastname: Thwaites
authors.forename: T T H
authors.initials: TT
authors.lastname: Chau
authors.forename: N T N
authors.initials: NT
authors.lastname: Lan
authors.forename: H T
authors.initials: HT
authors.lastname: Quy
authors.forename: N T
authors.initials: NT
authors.lastname: Hieu
authors.forename: A
authors.initials: A
authors.lastname: Aderem
authors.forename: T T
authors.initials: TT
authors.lastname: Hien
authors.forename: J J
authors.initials: JJ
authors.lastname: Farrar
authors.forename: S J
authors.initials: SJ
authors.lastname: Dunstan
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity; D020641:Polymorphism, Single Nucleotide; D051195:Toll-Like Receptor 2 / Q000235:genetics* / Q000378:metabolism; D014390:Tuberculosis, Meningeal / Q000235:genetics* / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000382:microbiology; D014744:Vietnam
chemical_list: D051195:Toll-Like Receptor 2