Genetic Mutation Identified for TB Vulnerability

About one in five people worldwide are infected with Mycobacterium tuberculosis, the bacterium that causes tuberculosis. Of those, only 10%, at most, will show symptoms, because most immune systems have tools to fight the microbe. When these tools are absent or dysfunctional, however, the infection can damage the lungs and other organs, and even cause death.

Genetic mutations have been uncovered that rob the immune system of its ability to combat more ubiquitous germs of the same bacterial family, mycobacteria. Molecular abnormalities have been elucidated that make people vulnerable to mycobacterial infections. This evidence points to strategies for treating or preventing some cases of tuberculosis (TB).


A large international team of scientists led by the Rockefeller University (New York, NY, USA) collected DNA samples from patients with active forms of the disease. By analyzing these samples, the team discovered that the risk of developing TB is heightened in people who have two copies of a particular variation to the gene coding for the enzyme tyrosine-protein kinase (TYK2).

The team reported that patients with autosomal recessive, complete interleukin (IL)-12Rβ2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. They showed that αβ T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. They also showed that the development of IFN-γ–producing CD4+ T cells, including, in particular, mycobacterium-specific TH1* cells (CD45RA−CCR6+), is dependent on both IL-12 and IL-23. They showed that the genes IL12RB1, IL12RB2, and IL23R have similar frequencies of deleterious variants in the general population.

Jean-Laurent Casanova, MD, PhD, a professor and senior author of the study, said, “In Europeans, one in 600 people have two copies of this TYK2 variation. And in the rest of the population the rate is between one in 1,000 to one in 10,000, which is still not rare. Here at Rockefeller, there are probably around four to six people who have this genetic predisposition to TB. Yet, that is not to say that those people will actually develop the disease, and, in fact, they probably won't. In New York, someone can have this mutation and their risk of getting TB is effectively zero. But if that person goes to work in a TB hospital in Africa, then the likelihood of getting TB is high, one hundredfold higher than it would be for a person without the genetic variant.” The study was published on December 21, 2018, in the journal Science Immunology.

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