Tuesday, March 17, 2015

TB's ability to evade immune system becomes clearer in large study

The largest-ever study to investigate the genes that influence susceptibility to tuberculosis has uncovered new clues about the biology behind its ability to evade the immune

The team behind the study - from research centers in the UK and Germany - hope the discovery will open new routes to
developing a vaccine for tuberculosis (TB).

They report their findings in the journal Nature Genetics.

TB infection is caused by the pathogen Mycobacterium
tuberculosis, which can spread to any organ in the body, but is
most commonly found in the lungs.

According to the World Health Organization (WHO), TB sickened 9 million and killed 1.5 million people in 2013. More than 95% of deaths to TB occur in low- and middle-income countries.

The UN agency estimates that around a third of the world's
population have latent TB, where the bacterium is in the body but does not flare up. Around 1 in 10 people with latent TB develop the active disease.

The leader of the new study, Dr. Sergey Nejentsev, a Wellcome Trust Senior Research Fellow in the Department of Medicine at the University of Cambridge in the UK, says: "TB is a major global health problem and the threat of drug-resistance means that we urgently need to develop new ways of fighting back."

Variants in ASAP1 gene affect susceptibility to TB infection

Dr. Nejentsev and colleagues wanted to further explore the idea that a person's DNA influences whether they are going to contract TB, both in terms of becoming infected with the bacterium and in terms of its development from latent to active TB.

Using a genome-wide association study (GWAS) they compared the genomes of 5,500 people with TB against 5,600 people without TB to identify genes that might increase susceptibility to TB.

After analyzing 7.6 million genetic variants - differences in sequences of DNA - they found variants in the gene ASAP1 on chromosome 8 that appear to affect a person's susceptibility
to TB.

ASAP1 codes for a protein that abounds in dendritic cells - a
type of immune cell that plays an important role in triggering
the appropriate immune response to an incoming pathogen.

The study shows that when a person is infected with M.
tuberculosis, their ASAP1 gene expresses less - it gets dimmer - and so produces less protein, which affects the ability of dendritic cells to trigger the immune response.

The researchers also found there are two variants of ASAP1; one is more protective than the other against TB. The less
protective one is associated with more reduction in gene
expression after TB infection, and the more protective one is
associated with less reduction in gene expression.

ASAP1 affects ability of dendritic cells to migrate and alert immune response

The team also found some clues about how ASAP1 affects
dendritic cells. When the gene expression is weakened, the cells cannot move so readily.

This explains why previous studies have found that dendritic cells in TB-infected people migrate very slowly.

Dendritic cells have to be able to move to alert cells in another part of the immune system to the presence of TB bacteria. If they are less able to move then they cannot trigger the appropriate immune response, allowing TB effectively to evade
the immune system.

Dr. Nejentsev says their study gives new clues about the
biological mechanisms of TB, and: The Wellcome Trust, the Royal Society, the EU Framework
Programme 7, the European Research Council, and the NIHR
Cambridge Biomedical Research Centre funded the study.

Meanwhile, Medical News Today recently learned of a study that showed drug-resistant TB may be treatable with a new small molecule drug. The researchers, from the University of Georgia in the US, believe the drug - which stops M. tuberculosis bacteria from growing and reproducing - may serve as a treatment against multidrug-resistant TB that cannot be cured with conventional drugs.