By combining the tools of nanotechnology and microbiology, the teams of Yves Dufrêne (FNRS, UCLouvain) and Jérôme Nigou (CNRS) have unraveled the sophisticated mechanism by which mycobacterial pathogens causing tuberculosis evade the immune system of the human host. In the future, these findings may help designing new anti- tuberculosis strategies.
The bacterial pathogen Mycobacterium tuberculosis, the causative agent of human tuberculosis kills a million people each year. New molecular knowledge on the infection process is urgently needed in order to develop better anti-mycobacterial therapies. To protect us from the pathogen, our immune cells are decorated with a family of proteins called pattern recognition receptors, of which the well-known DC-SIGN protein binds specific sugars (glycoligands) on the mycobacterial cell surface. Remarkably, mycobacteria have evolved ways to use this interaction to their own benefit, enabling them to escape the body’s immune system. While we know the structures of the exotic molecules involved and how they react at the population level in the test tube, we know little about how they bind in real life on the surfaces of immune cells. Using state-of-the-art atomic force microscopy, the researchers were able to map the distributions of glycoligands and DC-SIGN receptors with unprecedented single-molecule resolution. These molecular recognition imaging experiments demonstrated for the first time that glycoligands are concentrated into dense nanoscale domains on the mycobacterial surface. In addition, adhesion of bacteria to host cells was shown to induce the formation of large DC-SIGN clusters on immune cells. This study, published in Science Advances, highlights the key role of nanoclustering of both pathogen ligands and DC-SIGN host receptors, which is only possible to analyse through super-resolution, nanoscopy techniques. This fascinating mechanism might be widespread in pathogen-host interactions and may help designing new antituberculous strategies using immunomodulation.