Researchers identify how tuberculosis uses precision medicine to trick the immune system.

Tuberculosis is caused by the bacterium Mycobacterium tuberculosis and it affects over 12 million people globally. When the bacterium infects a person, the body’s immune response is critical to how the disease will progress; either helping the body fight the bacterium or, if certain key molecules become involved, actually exacerbating the infection. Now, EPFL researchers show how the tuberculosis bacterium co-opts mechanisms of the immune system to its own advantage. The opensource study is published in the journal Cell Host & Microbe.

The team state that when M. tuberculosis infects a person, it attacks the lungs’ first-response immune cells, the macrophages. The immune response by the macrophages involves a complex of four different proteins called the inflammasome. The main role of the inflammasome is to prepare certain immunity proteins in the macrophages, which are called interleukins. When M. tuberculosis infects the lungs, interleukins from the macrophages are in the first line of defense.

However, previous studies show that if it is left uncontrolled, this defense can also cause serious damage to the patient. To prevent this, macrophages also release another group of proteins called type I interferons. While interferons are important for defending the body against viruses, when it comes to tuberculosis they actually help the bacterium, thereby exacerbating the disease. And although the interleukin-inflammation part of the immune response is rather well documented, the part involving interferons has been elusive, state the team.

For the first time the current study shows how M. tuberculosis carries out a subtle assault on the immune defenses. The data findings show that the key is a molecule called cGAS, which is found in the lung’s macrophages, and is part of a group of DNA-sensor molecules; in short, cGAS patrols the inside of macrophages, and when it detects unidentified pieces of DNA, such as those released by M. tuberculosis, it triggers an immune response from the macrophages.

The tuberculosis bacterium uses a specialized secretion system to release its array of toxic proteins into macrophages. But, strangely, it also releases small bits of DNA, which are detected by sensing systems inside the macrophages, namely the inflammasome and cGAS. This causes macrophages to release two types of proteins; namely interleukin-1, which fights the bacterium, and type I interferons, which end up helping it.

The team used human and animal macrophages to study what happens when they are infected by M. tuberculosis. What they found was that the bacterium passes DNA bits into the macrophages, thereby tricking cGAS to signal the production of interferons, which reduce the immune response. In other words, the bacterium tricks the macrophages to cut back on their defense against it.  And the researchers did not stop there. They also showed that it is possible to manipulate M. tuberculosis in such a way that it can no longer activate the production of interferons through cGAS, while still keeping the production of interleukin-1, and thus the body’s immune response, intact.

The team state that the study is the first to identify cGAS as a sensor for M. tuberculosis DNA, and also suggests that this method of molecular manipulation applies to other bacteria that use specialized secretion systems to infect cells. The team surmise that the results show that tuberculosis is a far more sophisticated disease than previously thought and are now working, among other projects, to identify the DNA pieces that M. tuberculosis uses to trick macrophages.

Source:  École polytechnique fédérale de Lausanne  (EPFL)