The largest genetic study of tuberculosis (TB)susceptibility to date has led to a potentiallyimportant new insight into how the pathogenmanages to evade the immune system. Publishedtoday in the journal Nature Genetics, the studyadvances understanding of the biologicalmechanisms involved in TB, which may open upnew avenues to design efficient vaccines for itsprevention.
around one in ten of infected individuals developactive TB.
Evidence suggests that an individual's DNA affectstheir susceptibility to TB, both in terms of becominginfected and whether the disease progresses fromlatent to active TB. In order to identify genes thatpredispose people to TB, an international team ofresearchers carried out a genome-wide associationstudy (GWAS), comparing the genomes of 5,500TB patients against those of 5,600 healthy controls.In total, the researchers analysed 7.6 milliongenetic variants.
The team found that variants of the gene ASAP1 onchromosome 8 affect individuals' susceptibility toTB. The gene encodes a protein carrying the samename and is highly expressed - in other words,larger amounts of the protein are found - in aparticular type of immune cells known as dendriticcells that play a key role in kick-starting the body'simmune response to incoming pathogens.
The researchers showed that infection with M.tuberculosis leads to the reduction of ASAP1expression in dendritic cells - but people who havea particular genetic variant in the ASAP1 geneassociated with greater susceptibility to TB showstronger reduction of ASAP1 expression after infection than people who have a protective variantof this gene.
The researchers found that reducing levels of theASAP1 protein affects the ability of dendritic cells tomove, which explains the mechanism of thepreviously-known slow migration of dendritic cellsinfected with M. tuberculosis and may help thepathogen to evade the immune system, leading toTB.
Cambridge, who led the research. "TB is a majorglobal health problem and the threat of drug-resistance means that we urgently need to developnew ways of fighting back. In future, it may bepossible to target immune pathways that involveASAP1 to design efficient vaccines for TBprevention."
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