Genetic Association and Expression Studies Indicate a Role of Toll-Like Receptor 8 in Pulmonary Tuberculosis
Open Access
- 10 October 2008
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Genetics
- Vol. 4 (10) , e1000218
- https://doi.org/10.1371/journal.pgen.1000218
Abstract
Despite high rates of exposure, only 5–10% of people infected with Mycobacterium tuberculosis will develop active tuberculosis (TB) disease, suggesting a significant role for genetic variation in the human immune response to this infection. Here, we studied TB association and expression of 18 genes involved in the Toll-like receptor (TLR) pathways. Initially, we genotyped 149 sequence polymorphisms in 375 pulmonary TB patients and 387 controls from Indonesia. We found that four polymorphisms in the TLR8 gene on chromosome X showed evidence of association with TB susceptibility in males, including a non-synonymous polymorphism rs3764880 (Met1Val; P = 0.007, odds ratio (OR) = 1.8, 95% c.i. = 1.2–2.7). We genotyped these four TLR8 polymorphisms in an independent collection of 1,837 pulmonary TB patients and 1,779 controls from Russia and again found evidence of association in males (for rs3764880 P = 0.03, OR = 1.2, 95% c.i. = 1.02–1.48). Combined evidence for association is P = 1.2×10−3–6×10−4. In addition, a quantitative PCR analysis indicated that TLR8 transcript levels are significantly up-regulated in patients during the acute phase of disease (P = 9.36×10−5), relative to baseline levels following successful chemotherapy. A marked increase in TLR8 protein expression was also observed directly in differentiated macrophages upon infection with M. bovis bacille Calmette-Guérin (BCG). Taken together, our results provide evidence, for the first time, of a role for the TLR8 gene in susceptibility to pulmonary TB across different populations. One third of the world population is infected with Mycobacterium tuberculosis, the bacterium that causes tuberculosis; however, only 5–10% of those infected will develop active disease. Difference in polymorphisms within genes involved in host immune response has been proposed as a plausible reason to explain this phenomenon. Here, we show genetic association of four polymorphisms of TLR8, a member of a well-known receptor family involved in pathogen recognition, in an Indonesian population. The association was replicated in males of a follow up cohort from Russia. Expression levels of TLR8 transcripts and protein showed a marked increase during bacterial infection, confirming our initial findings. To our knowledge, this is the first time that TLR8 has been associated with response to M. tuberculosis. Our results suggest that it may play a significant role in tuberculosis susceptibility and disease activity, and thus should be the focus of concerted studies in human systems.Keywords
This publication has 38 references indexed in Scilit:
- Dynamic Changes in Pro- and Anti-Inflammatory Cytokine Profiles and Gamma Interferon Receptor Signaling Integrity Correlate with Tuberculosis Disease Activity and Response to Curative TreatmentInfection and Immunity, 2007
- Resequencing and association analysis of the SP110 gene in adult pulmonary tuberculosisHuman Genetics, 2006
- Linkage Disequilibrium Mapping of CHEK2: Common Variation and Breast Cancer RiskPLoS Medicine, 2006
- Haploview: analysis and visualization of LD and haplotype mapsBioinformatics, 2004
- Toll-like receptor signallingNature Reviews Immunology, 2004
- TLR9 signals after translocating from the ER to CpG DNA in the lysosomeNature Immunology, 2004
- The International HapMap ProjectNature, 2003
- The Toll‐like receptor 7 (TLR7)‐specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamilyEuropean Journal of Immunology, 2003
- Toll-like receptors and innate immunityNature Reviews Immunology, 2001
- Use and misuse of population attributable fractions.American Journal of Public Health, 1998