Full-Exon Resequencing Reveals Toll-Like Receptor Variants Contribute to Human Susceptibility to Tuberculosis Disease

Center for Human Bacterial Pathogenesis, Department of Pathology, Baylor College of Medicine, Houston, Texas, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2007; 2(12):e1318. DOI: 10.1371/journal.pone.0001318
Source: PubMed


Tuberculosis (TB) is the leading cause of death worldwide due to an infectious agent. Data have accumulated over decades suggesting that variability in human susceptibility to TB disease has a genetic component. Toll-like receptors (TLRs) play a critical role in initiating the innate immune response to many pathogens in mouse models, but little is known about their role in human infections. Human TLRs have been reported to recognize mycobacterial antigens and initiate an immune response. We tested the hypothesis that amino acid-altering polymorphisms in five TLRs were associated with susceptibility to TB disease using a population-based case-control study with 1,312 adult TB patients and controls. Full-coding region sequencing of the five TLR genes in all 1,312 subjects yielded a data set in excess of 16 Mb. Rare nonsynonymous polymorphisms in TLR6-TLR1-TLR10 were significantly overrepresented among African-American TB cases compared with ethnically-matched control subjects. Common nonsynonymous polymorphisms in TLR6-TLR1-TLR10 also were significantly associated with TB disease in certain ethnic groups. Among African Americans, homozygotes for the common-variant haplotype TLR1-248S, TLR1-602I, and TLR6-249S had a significantly increased TB disease risk. A transmission/disequilibrium test on an independent sample found that the TLR1-248S variant was preferentially transmitted to diseased children, thereby confirming disease association. These results are consistent with recent reports implicating TLR1 variants, including TLR1-602, in significantly altered innate immune responses. Also consistent with disease association, rare TLR6 variants were defective in their ability to mediate NF-kappaB signal transduction in transfected human cells. Taken together, the data suggest that variant TLRs contribute to human susceptibility to TB disease. Extensive full-exon resequencing was critical for revealing new information about the role of TLRs in human-pathogen interactions and the genetic basis of innate immune function.

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Available from: Edward A Graviss
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    • "Immunogenetics studies have also implicated other innate pathways, especially those related to pathogen sensing or cytokine and chemokine production, in immunity to mycobacterial infection. Polymorphisms in TLR2, TLR9 [91], TLR1 [92], TLR8 [93], and the intracellular signaling molecule TIRAP [94] have all been associated with susceptibility to mycobacterial infection. The mechanisms for the association between TLR and mycobacterial infection are still unclear and studies in the murine model of TB seem to indicate redundant roles for TLRs and TLR-associated molecules such as MyD88 in the generation of adaptive immune responses to Mtb [95] [96] [97] [98] [99] [100]. "
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    • "Hence, attempt was made to evaluate its frequency and significance in north Indian population and to look for its association with cases. Another SNP TLR6 745 C>T was chosen as it is present in extracellular domain of the TLR6 which is important in signaling [8] and reported to be associated with TB in American African population [11], again there is a single report from India on this polymorphism from south Indian population [13]. TLR1 1805 T>G was analysed in some of these subjects to clarify the linkage with TLR1 743 A>G. "
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    • "Certain mutations in the TLR genes, e.g. TLR1 and TLR6 are associated with an increased risk of acquiring M. tuberculosis[5,6]. In one study, host cells after exposure to M. tuberculosis were sensing the microbe-associated molecular pattern (MAMP) using independent PRRs like NOD2 and TLR. "
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