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

Abstract

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.

Lipidomic landscape in cancer: Actionable insights for membrane‐based therapy and diagnoses

“…It can be used to precisely identify molecular conformations, functional groups, bonding types, and intermolecular interactions. As each biomolecule absorbs at a particular wavelength, FTIR produces a signature spectral fingerprint spectra that permits investigating either the frequency (denoting the strength of interaction) or intensity (denoting the changes in local abundance) of vibrations/IR bands of associated biomolecules in the examined sample 158 . When coupled with unsupervised (e.g., principal component analysis [PCA]) or supervised (e.g., artificial neural networks) mathematical techniques and artificial intelligence, FTIR can provide superior diagnostic accuracy, specificity, and sensitivity 179,180 .…”

“…Complementary to image-based viscosity profiling are spectroscopy-based methods, which offer a quick screening of membrane viscosity using lipid probes and can easily be adapted to a high-throughput scale (Figure 4B). [156][157][158] The lipid probe diphenylhexatriene (DPH) intercalates near the acyl chains, with its charged counterpart trimethylamino (TMA)-DPH being 3-4 Å shallower than DPH. 159 Thus, DPH provides information on the hydrophobic acyl region and TMA-DPH on the interfacial head group region of the lipid membrane and can be used for the in-depth understanding of the mechanisms linking chemoresistance to microscopic viscosity changes.…”

“…As each biomolecule absorbs at a particular wavelength, FTIR produces a signature spectral fingerprint spectra that permits investigating either the frequency (denoting the strength of interaction) or intensity (denoting the changes in local abundance) of vibrations/IR bands of associated biomolecules in the examined sample. 158 When coupled with unsupervised (e.g., principal component analysis [PCA]) or supervised (e.g., artificial neural networks) mathematical techniques and artificial intelligence, FTIR can provide superior diagnostic accuracy, specificity, and sensitivity. 179,180 Backhaus et al 170 reported that analysis of sera samples with FTIR coupled with cluster analysis and artificial neural networks provided up to 98% sensitivity and 100% specificity for breast cancer diagnosis.…”

Lipoarabinomannan as a Point-of-Care Assay for Diagnosis of Tuberculosis: How Far Are We to Use It?

“…Reports indicate that mycobacterial species have different types of regulation of the complex array of lipids, which provide significant differences in both the architecture and fluidity of the membranes (Adhyapak et al, 2020). During Mtb infection, lipid (including LAM) regulation is related to the modification of the physical properties of host cell membranes through the incorporation and diffusion of Mtb lipids (Raghunandanan et al, 2019;Mishra et al, 2020).…”

Cationic inhalable particles for enhanced drug delivery to M. tuberculosis infected macrophages

“…However, the effect of varying surface charge of polymeric particles has not been studied with Mtb-infected macrophages. Given that Mtb infection has been known to modulate cytoskeletal proteins, cell membrane, phagocytic and endocytic machinery of the host, targeting strategies may differ between healthy and infected cells [29][30][31][32]. Through this study, we aim to design polymeric formulations that will be preferentially internalized by Mtb-infected cells and are optimal for in vivo delivery and uptake by immune cells through inhalation.…”