DEVELOPMENT OF NEW STRATEGIES TO FIGHT TUBERCULOSIS
Tuberculosis (Tb) is caused by Mycobacterium tuberculosis (Mtb) and remains one of the most deadly infectious diseases. The World Health Organization (WHO) estimates that in 2016, Tb killed 1.6 million people emphasizing the importance to develop new drugs, vaccines and diagnostic tools to reduce this burden in the future.
Mycobacteria depend on host lipids during infection, but precise knowledge of how Mtb and other pathogenic mycobacteria re-program lipid metabolic and lipid transport pathways to hijack host lipids is scarce.
Using the Dictyostelium/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 vacuole (MCV) to the cytosol recruit LD-derived enzymes and regulatory proteins on their hydrophobic surface. Previous work indicated that these pathogens not only hijack LDs, but also lipid metabolic enzymes and various components of the lipid trafficking machinery. However, a comprehensive understanding of the underlying molecular principles and their relevance for mycobacterial infection is missing at present.
Mycobacteria depend on host lipids during infection, but precise knowledge of how Mtb and other pathogenic mycobacteria re-program lipid metabolic and lipid transport pathways to hijack host lipids is scarce.
Using the Dictyostelium/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 vacuole (MCV) to the cytosol recruit LD-derived enzymes and regulatory proteins on their hydrophobic surface. Previous work indicated that these pathogens not only hijack LDs, but also lipid metabolic enzymes and various components of the lipid trafficking machinery. However, a comprehensive understanding of the underlying molecular principles and their relevance for mycobacterial infection is missing at present.
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left (modified from Shi et al. 2010):
Pathogenic mycobacteria undergo a metabolic switch upon infection torwards the use of host fatty acids to: - gain energy via the glyoxylate shunt - store energy in form of triacylglycerides - build up their hydrophobic membrane right: Lipid transfer from a phagocytic host cell to intracellular mycobacteria. Besides host triacylglycerides, also host sterols and phospholipids are manipuliated by mycobacteria. |
We will launch a first systematic effort to unravel the molecular mechanisms by which mycobacteria acquire and exploit host lipids using the Dictyostelium/M. marinum infection model. To this end, we will chart the lipid flows between mycobacteria and their host that are potentially relevant for infection and identify lipid species acquired by intracellular mycobacteria using metabolic tracing studies and mass spectrometry lipidomics. In addition, we plan to disrupt lipid flows from the host to the pathogen during infection using genetics or drugs. With the help of fluorescent and clickable lipid probes and modern microscopy techniques, we will first analyze the impact of these disruptions on host-to-pathogen lipid flows. Next, we will determine the consequences of blocking specific lipid supply routes on various stages of the mycobacterial infection course. Collectively, these efforts may uncover novel therapeutic targets to fight mycobacteria infection.
