Science

A research team in Lille has revealed a hitherto unknown strategy used by the tuberculosis bacterium to counteract the defenses of its host. A discovery which provides new information on the weaponry of this bacterium and paves the way for the development of new therapeutic avenues.

The tuberculosis bacterium, Mycobacterium tuberculosis, is a particularly efficient pathogen that can trigger infection with just a few bacilli. It has succeeded in infecting over one third of the world’s population! How do these bacteria manage to evade destruction by the immune cells and blithely colonize the cells of their hosts? An enigma that many researchers are trying to resolve. Today, research performed by Priscille Brodin* and her team at the Center for Infection and Immunity of Lille adds a new piece to the puzzle.

In order to neutralize an infectious element such as the tuberculosis bacillus, specialized immune system cells, known as macrophages, envelop and isolate it in a vesicle (called a phagosome) within their cytoplasm. Then begins a molecular process to acidify the contents of the vesicle, so that the ad-hoc enzymes can get to work and break down the intruder. But it turns out that the tuberculosis bacillus is capable of warding off this attack. It even manages to reproduce inside the macrophage and use it as a vector for its own dissemination.

Prevent phagosome acidification

Macrophage Tuberculose
Invasion of human macrophages (nuclei shown in blue) by the tuberculosis bacillus (in green) and its defense against acid attacks by the recruitment of the cell protein CISH (in red). The contour of a macrophage is represented by the dotted white line. © Queval CJ et al. Cell Rep. 2017. 13:3188-3198. CC-BY-NC-ND4.0

The change in pH inside the vesicle normally occurs thanks to a proton pump called V-ATPase. It hydrolyzes the ATP and transfers the H+ protons in the vesicle. Yet in the case of macrophages infected by M. tuberculosis this does not happen. In 2011, a Canadian team had already shown that the bacillus secretes a protein (called PtpA) which prevents the proton pump from joining forces with the vesicle membrane to release the H+ protons. Today, the team of Priscille Brodin, in collaboration with Edouard Yeramian, the team of Roland Brosch (Institut Pasteur in Paris), and Akihiko Yoshimura (Keio University, Tokyo), reveals a second strategy used by the bacillus: M. tuberculosis counteracts, for its own benefit, an immune response regulation process by stimulating the production of a protein (CISH), which destroys the V-ATPase. As a consequence, inhibiting this protein in an infected mouse macrophage reduces the proliferation of the bacillus.

The researchers have described the molecular cascade leading to the production of CISH: the bacillus acts on a cytokine (GM-CSF) which induces activation of the Stat5 protein. This protein then induces CISH expression.

These results provide new research avenues in the fight against a pathogen which has developed resistance to a number of antibiotics. However, what remains to be done is to determine any synergies between the two already-identified processes to neutralize the proton pump (dependent on PtpA and CISH proteins) and also identify other strategies that would explain the considerable capacity of the tuberculosis bacillus to control and maintain a pH favorable to its own replication. The researchers are also wondering about the existence of such cell-machinery diversion tactics with other pathogens.

Note

* unit 1019 Inserm/CNRS/Université de Lille 1/Institut Pasteur de Lille, Center for Infection and Immunity of Lille

Source

CJ Queval et coll. Mycobacterium tuberculosis controls phagosomal acidification by targeting CISH-mediated signalling. Cell Rep. 2017. 13:3188-3198.