A polymorphism in Toll-interleukin 1 receptor domain containing adaptor protein is associated with susceptibility to meningeal tuberculosis

Abstract

Background: Although meningitis is the most severe form of infection caused by Mycobacterium tuberculosis, the immunopathogenesis of this disease is poorly understood. We tested the hypothesis that polymorphisms in Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP), an adaptor protein that mediates signals from Toll-like receptors activated by mycobacteria, are associated with susceptibility to tuberculosis (TB).

Methods: We used a case-population study design in Vietnam with cord-blood control samples (n = 392) and case patients (n = 358) who had either pulmonary (n = 183) or meningeal (n = 175) TB.

Results: The TIRAP single-nucleotide polymorphism (SNP) C558T was associated with increased susceptibility to TB, with a 558T allele frequency of 0.035 in control samples versus 0.074 in case patients (odds ratio [OR], 2.25; P < .001). Subgroup analysis revealed that SNP 558T was more strongly associated with susceptibility to meningeal TB (OR, 3.02; P < .001) than to pulmonary TB (OR, 1.55; P = .22). In comparison to the 558CC genotype, the 558TT genotype was associated with decreased whole-blood interleukin-6 production, which suggests that TIRAP influences disease susceptibility by modulating the inflammatory response.

Conclusions: These results provide the first evidence of an association of a TIRAP SNP with the risk of any disease and also suggest that the Toll-like receptor pathway influences susceptibility to meningeal and pulmonary TB by different immune mechanisms.

Figure 1. Ex vivo whole-blood cytokine response and Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) single-nucleotide polymorphism (SNP) C558T.

Whole blood was harvested from individuals with TIRAP genotypes 558CC (black circles) or 558TT (white circles). Cells were stimulated with 80 or 320 ng/mL lipopeptides PAM2Cys-SKKK (PAM2) or PAM3Cys-SKKK (PAM3) (A), 10 ng/mL lipopolysaccharide (LPS) (B), PBS, or 25 or 100 μg/mL whole-cell H37Rv Mycobacterium tuberculosis (TB) lysates (C). Cells were stimulated for 18 h, and supernatants were assayed for cytokine production by ELISA. Data are combined from 2 separate experiments, each of which were performed in triplicate. Individual data points are plotted, with the median indicated by a line. Significant P values are noted and were calculated using the Mann-Whitney U test.