Lipid Dynamics during Mycobacteria Infection
Tuberculosis (Tb) is caused by Mycobacterium tuberculosis and remains one of the most deadly infectious diseases. The World Health Organization (WHO) estimates that in 2021, Tb killed 1.6 million people emphasizing the importance to develop new drugs, vaccines and diagnostic tools to reduce this burden in the future.
M. tuberculosis employs multiple strategies to survive intracellularly. One of its most striking adaptations is its ability to utilize host lipids such as fatty acids and sterols to: (i) generate energy, (ii) build its characteristic lipid-rich cell wall and (iii) produce storage lipids during infection. To be constantly in a fatty acid-rich environment, the pathogen actively contributes to generate the “foamy” phenotype in host macrophages, for which the accumulation of host lipid droplets (LDs) is characteristic.
Using the Dictyostelium discoideum/M. marinum infection system, we found that mycobacteria access host LDs to build up their own lipid storage organelles and exploit ER-derived phospholipids when LDs are lacking (Barisch et al., 2015; Barisch & Soldati, 2017). Moreover, we observed that mycobacteria that escaped from the Mycobacterium-containing vacuole (MCV) into the cytosol recruit LD-derived enzymes and regulatory proteins on their hydrophobic surface.
M. tuberculosis employs multiple strategies to survive intracellularly. One of its most striking adaptations is its ability to utilize host lipids such as fatty acids and sterols to: (i) generate energy, (ii) build its characteristic lipid-rich cell wall and (iii) produce storage lipids during infection. To be constantly in a fatty acid-rich environment, the pathogen actively contributes to generate the “foamy” phenotype in host macrophages, for which the accumulation of host lipid droplets (LDs) is characteristic.
Using the Dictyostelium discoideum/M. marinum infection system, we found that mycobacteria access host LDs to build up their own lipid storage organelles and exploit ER-derived phospholipids when LDs are lacking (Barisch et al., 2015; Barisch & Soldati, 2017). Moreover, we observed that mycobacteria that escaped from the Mycobacterium-containing vacuole (MCV) into the cytosol recruit LD-derived enzymes and regulatory proteins on their hydrophobic surface.
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KEY INTEREST
The Barisch lab aims to unravel the molecular mechanisms by which pathogenic mycobacteria acquire lipids from their host to support chronic infection. Combining the application of functionalized lipid probes, mass spectrometry-based lipidomics, and advanced microscopy techniques, we analyse metabolic lipid flows between mycobacteria and their host at the subcellular and ultrastructural levels.
Our research is grounded in three scientific pillars: mycobacteria, microscopy and lipids. |
Dgat2-GFP-labelled LDs interact with cytosolic mycobacteria (from Barisch and Soldati, 2017).
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LD interaction with cytosolic mycobacteria leads to the re-distribution of LD proteins on the mycobacterial surface (from Barisch and Soldati, 2017).
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Human Cell Models for Host-Pathogen Interaction
(Paulo Glatz & Josephina Offt)
(Paulo Glatz & Josephina Offt)
To translate findings from model organisms into human systems, we develop genetically engineered macrophages to study infection dynamics at high resolution. These models allow us to monitor organelle interactions, lipid signaling pathways and membrane trafficking during infection with M. marinum and M. tuberculosis. By combining advanced imaging with genetic manipulation and lipid biosensors, we aim to gain mechanistic insight into host defense strategies and identify potential intervention points.
M. marinum-infected human macrophages. Actin: grey, endosomes: blue, M. marinum: magenta.
Nutrional Immunity and Lipid Homeostasis
(Sylvana Hüttel & Miriam Ohlhagen)
(Sylvana Hüttel & Miriam Ohlhagen)
We investigate how host cells control lipid availability during infection as a form of nutritional immunity. Mycobacteria rely on host-derived fatty acids, yet the regulation and compartmentalization of these lipids can influence bacterial survival. We explore how perturbations in host lipid metabolism—especially in enzymes involved in fatty acid activation—affect mycobacterial access to nutrients, vacuole stability, and cytosolic escape. These studies aim to uncover host strategies that restrict mycobacterial growth by modulating lipid environments. This project is part of the SPP2225.
Lipid Droplet Interactions in Infection
(Aby Anand)
(Aby Anand)
Lipid droplets in human macrophages moving along microtubles.
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Lipid droplets (LDs) play a central role in mycobacterial infection. We study how LDs interact with the Mycobacterium-containing vacuole (MCV) and how their dynamics are altered during infection. Using both Dictyostelium and macrophages, we monitor LD recruitment, turnover and lipid transfer, employing cryo-correlative light and electron microscopy (cryo-CLEM), tomography, and live-cell imaging. My goal is to understand how mycobacteria manipulate host LD metabolism to support their intracellular persistence.
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Membrane-Contact Sites and Lipid Transfer
(Anna-Carina Mazur & Jonas Jerke)
(Anna-Carina Mazur & Jonas Jerke)
Intracellular mycobacteria induce membrane damage and establish contacts with host organelles to access lipids. We focus on ER-derived membrane-contact sites (MCSs) and the role of lipid transfer proteins during infection. Specifically, we investigate the formation and function of tethering complexes, including VAP-mediated interactions and their contribution to lipid transport across organelle interfaces. By combining ultrastructural imaging and functional assays, we aim to dissect how mycobacteria exploit host MCSs for nutrient acquisition. This project is part of the SFB1557.
Therapeutic Targeting of Mycobacteria (with Gutsmann (FZB) and Meier (UHH) labs)
(Lena Gonner)
(Lena Gonner)
We explore innovative strategies to target the unique lipid-rich envelope of mycobacteria. One avenue is the development of antimicrobial peptides (AMPs) enhanced with targeting motifs specific to the mycobacterial membrane. These approaches aim to improve the delivery and efficacy of AMPs against drug-resistant strains of M. tuberculosis. Our efforts contribute to the design of novel therapeutic tools that disrupt host-pathogen lipid interactions. This project is part of the CSSB-tagin cohort against infections.
