Mycobacterium Lipids Modulate Host Cell Membrane Mechanics, Lipid Diffusivity, and Cytoskeleton in a Virulence-Selective Manner

Microbial lipids play a critical role in the pathogenesis of infectious diseases by modulating the host cell membrane properties, including lipid/protein diffusion and membrane organization. Mycobacterium tuberculosis (Mtb) synthesizes various chemically distinct lipids that are exposed on its outer membrane and interact with host cell membranes. However, the effects of the structurally diverse Mtb lipids on the host cell membrane properties to fine-tune the host cellular response remain unknown. In this study, we employed membrane biophysics and cell biology to assess the effects of different Mtb lipids on cell membrane mechanics, lipid diffusion, and the cytoskeleton of THP-1 macrophages. We found that Mtb lipids modulate macrophage membrane properties, actin cytoskeleton, and biochemical processes, such as protein phosphorylation and lipid peroxidation, in a virulence lipid-selective manner. These results emphasize that Mtb can fine-tune its interactions with the host cells governed by modulating the lipid profile on its surface. These observations provide a novel lipid-centric paradigm of Mtb pathogenesis that is amenable to pharmacological inhibition and could promote the development of robust biomarkers of Mtb infection and pathogenesis.