Nanoscale clustering of mycobacterial ligands and DC-SIGN host receptors are key determinants for pathogen recognition.

Abstract

The bacterial pathogen <i>Mycobacterium tuberculosis</i> binds to the C-type lectin DC-SIGN (dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin) on dendritic cells to evade the immune system. While DC-SIGN glycoconjugate ligands are ubiquitous among mycobacterial species, the receptor selectively binds pathogenic species from the <i>M. tuberculosis</i> complex (<i>MTBC</i>). Here, we unravel the molecular mechanism behind this intriguing selective recognition by means of a multidisciplinary approach combining single-molecule atomic force microscopy with Förster resonance energy transfer and bioassays. Molecular recognition imaging of mycobacteria demonstrates that the distribution of DC-SIGN ligands markedly differs between <i>Mycobacterium bovis</i> Bacille Calmette-Guérin (BCG) (model <i>MTBC</i> species) and <i>Mycobacterium smegmatis</i> (non-<i>MTBC</i> species), the ligands being concentrated into dense nanodomains on <i>M. bovis</i> BCG. Upon bacteria-host cell adhesion, ligand nanodomains induce the recruitment and clustering of DC-SIGN. Our study highlights the key role of clustering of both ligands on <i>MTBC</i> species and DC-SIGN host receptors in pathogen recognition, a mechanism that might be widespread in host-pathogen interactions.