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).
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.
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.
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.
"The synonymous Tirap SNP, C558T (Ala186 Ala), has also been linked to increased susceptibility to tuberculosis. Individuals with the 558TT genotype had decreased levels of interleukin-6 in whole-blood . "
[Show abstract][Hide abstract] ABSTRACT: Toll-like receptors (TLRs), a large group of proteins which recognize various pathogen-associated molecular patterns, are critical for the normal function of the innate immune system. Following their discovery many single nucleotide polymorphisms within TLRs and components of their signaling machinery have been discovered and subsequently implicated in a wide range of human diseases including atherosclerosis, sepsis, asthma, and immunodeficiency. This review discusses the effect of genetic variation on TLR function and how they may precipitate disease.
Current Genomics 12/2012; 13(8):633-45. DOI:10.2174/138920212803759712 · 2.34 Impact Factor
"Interleukin-1β up-regulates essential mediators necessary for the control M.tb infection including iNOS and subsequent NO production (Chan et al., 2001), phagosomal acidification and maturation (Horsburgh Jr., 1991), adhesion molecules (Dinarello, 2009), and enzymatic activities like phospholipase A 2 and cyclooxygenase (Hernandez-Pando et al., 2006; Yang et al., 2009). Human studies (Gomez et al., 2006; Hawn et al., 2006; Settas et al., 2007) and in vivo studies using IL-1Ra (receptor antagonist) and IL-1α/IL-1β deficient mice (Juffermans et al., 2000; Yamada et al., 2000; Fremond et al., 2007) established that the continuous effect of IL-1 is required for maintaining resistance to M.tb infection. IL-6 is mainly considered to be a proinflammatory cytokine involved in macrophage and cytotoxic T cell differentiation. "
[Show abstract][Hide abstract] ABSTRACT: Tuberculosis is still a major health problem in the world. Initial interactions between Mycobacterium tuberculosis and the host mark the pathway of infection and the subsequent host inflammatory response. This inflammatory response is tightly regulated by both the host and the bacterium during different stages of infection. As infection progresses, the initial intense pro-inflammatory response observed is regulated by suppressive mediators balancing inflammation. In this environment, M. tuberculosis battles to survive interfering with the host inflammatory response. In this review we discuss the major effector molecules involved in inflammation in relation to the different stages of M. tuberculosis infection.
Frontiers in Microbiology 01/2011; 2:2. DOI:10.3389/fmicb.2011.00002 · 3.99 Impact Factor
"Our results are similar to those of some association studies of this variation in other populations, which also found no correlation of SNP with TB in Russian, Ghanaian, Indonesian (Nejentsev et al., 2008), and Vietnamese (Hawn et al., 2006) in a large scale of samples. For the SNP C558T, another study provided evidence showing that both the variant and the haplotype containing the T allele were more frequent in TB patients than in controls (Hawn et al., 2006). In our study, although both the T allele (OR = 1.55; "
[Show abstract][Hide abstract] ABSTRACT: Toll-interleukin 1 receptor (TIR) domain containing adaptor protein (TIRAP; also known as MAL) is an essential adaptor molecule in Toll-like receptor signaling, involved in activating the innate immune response during infection. Genetic variations in the TIRAP gene may influence human susceptibility to infectious disease. To date, in the Chinese population, a possible predisposition of TIRAP gene variants to tuberculosis has not been reported. We investigated whether TIRAP gene polymorphisms are associated with the development of tuberculosis in a Chinese population. We investigated all the single-nucleotide polymorphisms (SNPs) within the TIRAP exon 5 in a case-control study of 212 patients with tuberculosis and 215 controls in a Chinese population. Genotyping was performed to identify the polymorphisms of TIRAP gene by PCR-DNA sequencing method. Haplotypes for the TIRAP gene variants were constructed using Haplo view version 4.2. Six polymorphisms of the SNPs listed in the National Center for Biotechnology Information database were detected in these Chinese tuberculosis patients. It was found that both the frequency of the 286A allele (odds ratio (OR) = 13.37; 95% confidence interval (CI) = 0.75-238.3; P < 0.01) and the frequency of 286AG genotype (OR = 13.57; 95%CI = 0.76-242.5; P < 0.01) were significantly higher in patients than in healthy controls. However, two other SNPs, C539T and C558T, reported to be associated with tuberculosis in other populations, were found not to be associated with tuberculosis in this Chinese population. We conclude that TIRAP G286A (D96N) polymorphism is associated with susceptibility to tuberculosis and may be a new risk factor for the development of tuberculosis in China.
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