Abstract
Host recognition of mycobacterial surface molecules occurs through toll like receptors (TLR) 2 and 6. The adaptor protein TIRAP mediates down stream signalling of TLR2 and 4, and polymorphisms in the TIRAP gene (TIRAP) have been associated with susceptibility and resistance to tuberculosis (TB) in adults. In order to investigate the role of polymorphic variation in TIRAP in childhood TB in South Africa, which has one of the highest TB incidence rates in the world, we screened the entire open reading frame of TIRAP for sequence variation in two cohorts of childhood TB from different ethnic groups (Xhosa and mixed ancestry). We identified 13 SNPs, including seven previously unreported, in the two cohorts, and found significant differences in frequency of the variants between the two ethnic groups. No differences in frequency between individual SNPs or combinations were found between TB cases and controls in either cohort. However the 558C→T SNP previously associated with TB meningitis (TBM) in a Vietnamese population was found to be associated with TBM in the mixed ancestry group. Polymorphisms in TIRAP do not appear to be involved in childhood TB susceptibility in South Africa, but may play a role in determining occurrence of TBM.
Highlights
Activation of host inflammatory responses are fundamental to containment of Mycobacterium tuberculosis (MTB) following initial infection [1]
We identified thirteen single nucleotide polymorphism (SNP) across the TIR-domain-containing adapter like protein (TIRAP) gene of which only seven have previously been identified
The minor allele frequency (MAF) of the majority of SNPs was low (,0.05) with only 760ARG and 820CRT having a higher frequency in both groups and the 558CRT in the mixed ancestry group only
Summary
Activation of host inflammatory responses are fundamental to containment of Mycobacterium tuberculosis (MTB) following initial infection [1]. The majority of individuals who are exposed to MTB successfully contain the infection and remain asymptomatic but latently infected throughout life. TB disease develops in a minority of those infected, either following the primary infection or due to reactivation of latent disease many years later [2]. Differences in immune response genes are believed to be important in determining whether an individual successfully contains the infection or develops disease [3,4,5], but the genes responsible remain largely unknown. The ability to rapidly activate innate immune responses is likely to be critical in the containment of mycobacteria during primary infection in childhood, as evidenced by the unique susceptibility to mycobacteria in patients with Mendelian defects in interferon gamma (IFNc) and interleukin 12 (IL-12) pathways [9,10,11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
