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Genetic Association and Expression Studies Indicate a Role of Toll-Like Receptor 8 in Pulmonary Tuberculosis

30 Oct 2008

Marcia Triunfol

Source: PLoS Genetics (see original article)

Citation: Davila S, Hibberd ML, Hari Dass R, Wong HEE, Sahiratmadja E, et al. (2008). Genetic Association and Expression Studies Indicate a Role of Toll-Like Receptor 8 in Pulmonary Tuberculosis. PLoS Genet 4(10): e1000218.

Pathogen recognition is considered by many as the key element that determines infection outcome. In other words, depending on the host’s ability to recognize the invading pathogen, an infection may or may not develop into a full-blown crisis. Alternatively, the infection might be kept latent.

Additional research has shown that toll-like receptors (TRL) are implicated in the recognition of pathogen-associated molecules. It is believed that this occurs through a cascade of events that lead to the transcription of key genes that play important roles in inflammation.

It is estimated that one third of the world’s population is infected with Mycobacterium tuberculosis. Nevertheless, only 10% or so actually develop the disease. The remaining 90% have what is known as latent tuberculosis.

To investigate whether TRLs are associated with susceptibility to develop tuberculosis, a group of researchers looked for genetic polymorphisms in the DNA sequences of human TRLs that could be used in association analysis.

Four single nucleotide polymorphisms (SNPs) found in the TRL8 were tested in two different populations; a large sample of patients from Russia and an Indonesian population.

All four SNPs showed to be significant, which means that these four single-spot changes occurring in the DNA sequence of TRL8 are unlikely to have occurred by chance alone. One of these SNPs called rs3764880 showed a strong association with pulmonary tuberculosis. Patients carrying this variant presented an increased chance of developing the disease.

The fact that the association between TRL8 and tuberculosis is even greater in men than in women supports the involvement of TRL8 in pulmonary TB, as the TRL8 gene is located on the X chromosome. As with X-linked diseases that are predominant in males because they carry only one copy of the X chromosome in their cells, instead of two, the risk for developing tuberculosis should also be greater in males. Because women have two X chromosomes, a deleterious effect caused by an allele in one X can be compensated by a normal allele in the other X.

The study also showed that TRL8 mRNA levels are also increased during acute disease, whereas protein expression was increased in macrophage cell lines after infection with BCG. These are additional evidences of the involvement of TRL8 in the development of pulmonary TB.

The study is the first to show strong evidence that TRL8 indeed plays a role in the establishment of TB, although the details of such involvement need to be further investigated.

2008 Davila et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Source

Title:
Genetic association and expression studies indicate a role of toll-like receptor 8 in pulmonary tuberculosis.

Authors:
Davila S, Hibberd ML, Hari Dass R, Wong HE, Sahiratmadja E, Bonnard C, Alisjahbana B, Szeszko JS, Balabanova Y, Drobniewski F, van Crevel R, van de Vosse E, Nejentsev S, Ottenhoff TH, Seielstad M

References:
PLoS Genet. Oct 2008: Vol. 4 no. 10, pp. e1000218

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 = 1.2x10(-3)-6x10(-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 = 9.36x10(-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.

PMID: 18927625
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