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.
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.
Lipids form an integral, structural, and functional part of all life forms. They play a significant role in various cellular processes such as membrane fusion, fission, endocytosis, protein trafficking, and protein functions. Interestingly, recent studies have revealed their more impactful and critical involvement in infectious diseases, starting with the manipulation of the host membrane to facilitate pathogenic entry. Thereafter, pathogens recruit specific host lipids for the maintenance of favorable intracellular niche to augment their survival and proliferation. In this review, we showcase the lipid-mediated host pathogen interplay in context of life-threatening viral and bacterial diseases including the recent SARS-CoV-2 infection. We evaluate the emergent lipid-centric approaches adopted by these pathogens, while delineating the alterations in the composition and organization of the cell membrane within the host, as well as the pathogen. Lastly, crucial nexus points in their interaction landscape for therapeutic interventions are identified.
Mycobacterium tuberculosis (Mtb) serves as the epitome of how lipidsnext to proteinsare utilized as central effectors in pathogenesis. It synthesizes an arsenal of structurally atypical lipids (C60−C90) to impact various membrane-dependent steps involved in host interactions. There is a growing precedent to support insertion of these exposed lipids into the host membrane as part of their mode of action. However, the vital role of specific virulence-associated lipids in modulating cellular functions by altering the host membrane organization and associated signaling pathways remain unanswered questions. Here, we combined chemical synthesis, biophysics, cell biology, and molecular dynamics simulations to elucidate host membrane structure modifications and modulation of membrane-associated signaling using synthetic Mycobacterium tuberculosis sulfoglycolipids (Mtb SL). We reveal that Mtb SL reorganizes the host cell plasma membrane domains while showing higher preference for fluid membrane regions. This rearrangement is governed by the distinct conformational states sampled by SL acyl chains. Physicochemical assays with SL analogues reveal insights into their structure−function relationships, highlighting specific roles of lipid acyl chains and headgroup, along with effects on autophagy and cytokine profiles. Our findings uncover a mechanism whereby Mtb uses specific chemical moieties on its lipids to fine-tune host lipid interactions and confer control of the downstream functions by modifying the cell membrane structure and function. These findings will inspire development of chemotherapeutics against Mtb by counteracting their effects on the host-cell membrane.
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