TY - JOUR TI - Spreading of a mycobacterial cell-surface lipid into host epithelial membranes promotes infectivity AU - Cambier, CJ AU - Banik, Steven M AU - Buonomo, Joseph A AU - Bertozzi, Carolyn R A2 - Stallings, Christina L A2 - Soldati-Favre, Dominique A2 - Oehlers, Stefan H VL - 9 PY - 2020 DA - 2020/11/23 SP - e60648 C1 - eLife 2020;9:e60648 DO - 10.7554/eLife.60648 UR - https://doi.org/10.7554/eLife.60648 AB - Several virulence lipids populate the outer cell wall of pathogenic mycobacteria. Phthiocerol dimycocerosate (PDIM), one of the most abundant outer membrane lipids, plays important roles in both defending against host antimicrobial programs and in evading these programs altogether. Immediately following infection, mycobacteria rely on PDIM to evade Myd88-dependent recruitment of microbicidal monocytes which can clear infection. To circumvent the limitations in using genetics to understand virulence lipids, we developed a chemical approach to track PDIM during Mycobacterium marinum infection of zebrafish. We found that PDIM's methyl-branched lipid tails enabled it to spread into host epithelial membranes to prevent immune activation. Additionally, PDIM’s affinity for cholesterol promoted this phenotype; treatment of zebrafish with statins, cholesterol synthesis inhibitors, decreased spreading and provided protection from infection. This work establishes that interactions between host and pathogen lipids influence mycobacterial infectivity and suggests the use of statins as tuberculosis preventive therapy by inhibiting PDIM spread. KW - Mycobacteria KW - bioorthogonal chemistry KW - PDIM JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -