The conical shape of DIM lipids promotesMycobacterium tuberculosisinfection of macrophages

Phthiocerol dimycocerosate (DIM) is a major virulence factor of the pathogenMycobacterium tuberculosis(Mtb). While this lipid promotes the entry ofMtbinto macrophages, which occurs via phagocytosis, its molecular mechanism of action is unknown. Here, we combined biophysical, cell biology, and modeling approaches to reveal the molecular mechanism of DIM action on macrophage membranes leading to the first step ofMtbinfection. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry showed that DIM molecules are transferred from theMtbenvelope to macrophage membranes during infection. Multiscale molecular modeling and31P-NMR experiments revealed that DIM adopts a conical shape in membranes and aggregates in the stalks formed between 2 opposing lipid bilayers. Infection of macrophages pretreated with lipids of various shapes uncovered a general role for conical lipids in promoting phagocytosis. Taken together, these results reveal how the molecular shape of a mycobacterial lipid can modulate the biological response of macrophages.