The bacterium that causes tuberculosis has a mechanism to block the immune response when it infects an organism, allowing it to proliferate. This system has now been uncovered thanks to a 3D model of its structure.
This is a long-awaited finding among researchers dealing with tuberculosis, as “it could help revolutionize the search for new treatments against this and other bacterial diseases,” according to the National Oncology Research Center (CNIO), which participated in the discovery.
The multidisciplinary study, published by Nature and in which the German University of Würzburg also collaborated, opens the possibility of developing a new generation of compounds that, instead of destroying bacteria as antibiotics do, block their virulence.
New therapeutic strategies
About 10 million people got tuberculosis in the world during 2017, of which 1.6 million died. The current treatment is 40 years old and strains have emerged that show resistance, so it is urgent to find new therapeutic strategies.
For this, it is necessary to understand in depth the mechanisms that bacteria use to cause the disease, the CNIO said in a statement.
When an organism is infected by Mycobacterium tuberculosis, the immune system launches a complex response to destroy it, but the bacterium has sophisticated mechanisms to weaken it, including a secretion system that injects certain virulence factors into immune cells. These factors are molecules which task is to paralyze the defensive response of immune cells, so that, instead of being destroyed, bacteria have a free way to continue infecting the body.
Until now, the structure and operating mechanism of that secretion system, called T7SS, were not studied in detail. It was only known that it was shaped like a six-pointed star (hexameter), which center serves as a channel through which the bacterium expels virulence factors.
Now thanks to the work of Óscar Llorca and Ángel Rivera-Calzada, of the CNIO, and Sebastian Geibel and Nikolaos Famelis of the University of Würzburg, T7SS is described at atomic level.
A sophisticated nanomachine
The researchers worked with the bacteria M. smegmatis, which is used in research as a model to study M. tuberculosis and shares with it the same secretion system.
The work showed that T7SS constitutes a sophisticated nanomachine where several proteins cooperate for the injection of virulence factors in the cells of the immune system.
The Spanish team are experts in electronic cryomicroscopy, a technique that allows to obtain images of molecular structures at a high resolution, thanks to which they have detailed all the actors involved in the T7SS.
In addition, they have identified function of some of them (which remained unknown), have modeled their structure in three dimensions and, based on all this information, have proposed an operating mechanism.
“We have seen that the components that until now were diffuse with other techniques are actually elements that are in constant motion,” explains Llorca.
The proposed operating mechanism was successfully tested by the University of Würzburg. The system used by the German center is of great interest for the entire research community to test the effect of new molecules directed against this secretion mechanism, which need the bacteria of the genus Mycobacterium to successfully carry out the infection, said Rivera-Calzada.
The CNIO team and the University of Würzburg will now try to study in greater depth how the secretion process occurs in Mycobacterium, to open the way to the design of molecules that can block it.
Source: Agencia ID
