What do Frédéric Chopin, Franz Kafka, and Nelson Mandela have in common? What sounds like a trivia question is at the heart of a long-standing mystery for infectious disease researchers. All three fell ill with tuberculosis (TB), which makes them an interesting minority. After all, only one in 10 people who are infected with the TB-causing bacterium Mycobacterium tuberculosis ever develops the disease. So what distinguishes those who get sick from those who don’t?
Now, scientists may have found one answer: a set of 16 genes that is more active in people who will develop TB in the next 1 or 2 years than in those who are infected but stay healthy. "It’s a real breakthrough," says Barry Bloom, a veteran of the fight against TB at the Harvard T. H. Chan School of Public Health in Boston who wasn't involved in the study. Knowing who will develop TB—and potentially spread it—could help target interventions, Bloom says; it could also make research on new therapeutics easier and cheaper.
More than 2 billion people—almost a third of the world's population—carry M. tuberculosis, and an estimated 1.5 million died from it in 2014, making TB the deadliest infectious disease in the world. But predicting who'll be unlucky enough to fall ill has so far been impossible.
To find a predictive signature, scientists took advantage of a large study of more than 6000 young people at risk of TB who were followed in South Africa for at least 2 years. The researchers compared blood samples from 37 people who developed TB and 77 others who carried M. tuberculosis but remained healthy; they discovered 16 genes that were more active in the former group. They then tested how well the signature held up in another nine participants who had developed TB and 30 who didn’t. The test confirmed the predictive power of the gene signature; another test in independent groups in Gambia and South Africa also validated the test, the team reports today in The Lancet.
The predictions are far from perfect. Overall, the gene signature picked out only about 80% of infected people who would go on to develop TB in the next 12 months, and it also wrongly fingered about one-third of the people who would remain healthy. And the longer before the disease developed, the less accurate the test became.
Still, "this is an exciting study,” says Helen Fletcher, director of the TB center at the London School of Hygiene & Tropical Medicine. Because people only become infectious after they have fallen ill, the research may provide a way to detect and treat TB before it can be spread from one person to another, she says. Bloom agrees; now, "there should be trials to establish whether those with the gene signature [predicting disease], if treated with anti-TB drugs, can be cured before developing active disease,” he says. (Because there are so many infected people and TB treatment consists of several drugs taken for up to 9 months, most people currently don't get treatment unless they get sick.)
Such trials are already being planned, says Willem Hanekom of the Bill & Melinda Gates Foundation in Seattle, Washington, one of the study's authors. “The signature does not have to be 100% specific and sensitive for interventions to work," he says. The current accuracy may be enough to start people on isoniazid, a drug given to prevent TB, Fletcher says, but not to give them full TB treatment, which is associated with more side effects. The test kit itself needs a lot of work, too, she adds; it has to be made affordable and easy to use at any clinic.
The 16 genes include several well-known inflammation genes, suggesting that the signature may be an early sign that TB is developing. But there is more to it than just inflammation, Hanekom says. “There may be other things in the environment of these patients that trigger this signature long before TB disease," he says. "We just don’t know, but in terms of interventions it doesn’t really matter.“
The test could also be a boon for TB research, says Stefan Kaufmann of the Max Planck Institute of Infection Biology in Berlin, one of the authors. Testing therapeutic vaccines and other interventions is an expensive undertaking requiring huge study groups, he says. Including only people with the high-risk genetic signature could make the research much cheaper. “Even if you only have twice the number of people developing tuberculosis that you would normally have,” he says, “that is a big help.”