Abstract
Toll like receptors (TLR) are key elements of the innate immune response and involved in the recognition of pathogens. To test common and rare TLR variants involved in susceptibility or resistance to infection with Mycobacterium tuberculosis we screened the exons of the genes encoding TLR 1, 2, 4, and the adaptor molecule TIRAP in more than 4500 tuberculosis (TB) cases and controls from Ghana. The analysis yielded 109 variants with possible functional impact, including 101 non-synonymous variants, three stop-variants, and five indels. Association analyses yielded a significant result for the TLR1 variant rs3923647, conferring strong protection against TB (Odds ratio [OR] 0.21, CI confidence interval [CI] 0.05–0.6, Pnominal 1 x 10−3) when applying a recessive model of inheritance. Replication analyses with an additional 3370 Ghanaian cases and control samples, and with data from a recent TB study of 533 African-Americans confirmed the protective effect and resulted in a combined OR of 0.19, with a nominal P value of 2.2 x 10−5, and a corrected P value of 4.1 x 10−4. The SNP is located near the binding pocket of TLR1 and causes an amino acid exchange from histidine to leucine at position 305. The observed effect may, therefore, be attributable to structural changes in the recognition site of the TLR1 molecule, allowing to bind those mycobacterial ligands which preferentially may induce a protective immune response. This is supported by the analysis of BCG-stimulated peripheral blood mononuclear cells, showing increased induction of the proinflammatory cytokine IFN-γ in carriers of the mutant TLR1 rs3923647 TT genotype, compared to the IFN-γ levels of individuals with the AT and AA genotypes.
Highlights
Tuberculosis (TB) remains a global threat with more than one third of the world’s population infected with Mycobacterium tuberculosis
We extensively screened for SNPs of toll like receptor (TLR) 1, 2, 4 and TIRAP to analyse the contribution of rare and common variants in TB
The non-synonymous TLR1 variant H305L was strongly associated with protection from M. tuberculosis infection when applying a recessive model of inheritance
Summary
Tuberculosis (TB) remains a global threat with more than one third of the world’s population infected with Mycobacterium tuberculosis. Factors playing a decisive role in the development of clinically manifest infections include environmental risks, the pathogens virulence, and the immune status and genetic architecture of the host [1,2,3,4,5,6]. Distinct binding specificities of each TLR subtype allow to recognize a variety of evolutionarily conserved molecules, addressed as pathogen-associated molecular patterns (PAMPs) [7,8]. PAMPs form a diverse group of molecules, among them immunogenic compounds of pathogens, including LPS, glycolipids, lipoproteins, flagellin, RNA and DNA and others [9]. Downstream signal transduction processes are triggered by binding of cytosolic adaptor molecules such as MyD88, TIRAP, and TRIF to the intracellular Toll-interleukin 1 (IL-1) receptor (TIR) domain. The TLR signal cascade, through activation of the transcription factor Nf-κB, induces secretion of proinflammatory cytokines [9]
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