Abstract
Lipids dictate membrane properties to modulate lateral membrane organization, lipid/protein diffusion and lipid-protein interactions, thereby underpinning proper functioning of cells. Mycobacterium tuberculosis harnesses the power of its atypical cell wall lipids to impact immune surveillance machinery centered at the host cell membrane. However, the role of specific virulent lipids in altering host cellular functions by modulating membrane organization and the associated signaling response are still pertinent unresolved questions. Here, combining membrane biophysics and cell biology, we elucidate how virulent Mtb sulfoglycolipids hijack the host cell membrane, affecting its order, fluidity, and stiffness along with manipulating the linked cytoskeleton. The functional outcome of this perturbation was assayed by monitoring membrane-associated autophagy signaling. These actions form a part of the overall response to commandeer host membrane-associated immune processes during infection. The findings on the mechanism of action of Mtb lipids on host cell membrane structure and downstream signaling will deepen the collective understanding of their functional aspects in membrane-dictated bacterial survival, pathogenesis and drug resistance and reveal suitable membrane driven-therapeutic intervention points and diagnostic tools.
Highlights
More recently the indirect mechanism of perturbing host cell function by Mycobacterium tuberculosis (Mtb) lipids propose their insertion into the host membranes impairing their biophysical properties and leading to altered activities of membrane-bound effectors and modulated membrane-associated signaling[3,11]
Using methyl-β cyclodextrin (MβCD) which causes cholesterol depletion from the cellular PM34 we identified that the ordered Generalized Polarization (GP) population discernible in the global GP distribution was most affected by this treatment, leading to a shift to lower GP values with a significant reduction of its surface coverage within 30 minutes of incubation (Fig. S3 and Table S2)
Various studies have highlighted intimate crosstalk of the cell’s plasma membrane (PM) and the underlying actin filaments attuning many physiological processes[37,39]. Given these facts and our observation of dynamic reshaping of the host cell membrane, we investigated the effect of SL-1-membrane interaction on the actin cytoskeleton in THP-1 macrophages
Summary
More recently the indirect mechanism of perturbing host cell function by Mtb lipids propose their insertion into the host membranes impairing their biophysical properties and leading to altered activities of membrane-bound effectors and modulated membrane-associated signaling[3,11]. The data highlights a unique pattern of interaction of structurally diverse Mtb lipids with host cell membrane that leads to distinct effects including altered membrane fluidity, permeability, reorganization of lipid domains, and disruption of bilayer ordering. Given this progress, little is known about the most abundant sulfatide in the Mtb outer membrane, Sulfoglycolipid-1, SL-1 (Fig. 1A), a tetra-acylated trehalose-based lipid. The effect percolates to the actin cytoskeleton underneath the membrane, and leads to activated autophagy signaling This result aligns with the work by Lee et al, that revealed direct engagement of total Mtb lipids and not proteins from different bacterial strains in tempering with host autophagy[24]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
