Project: Functional impact of mycobacterial cell wall components on the infection of Dictyostelium discoideum with Mycobacterium marinum

  Copyright: © Barisch

Tuberculosis is caused by Mycobacterium tuberculosis (Mtb) and is responsible for 1.6 million deaths worldwide every year. The infection is initiated when Mtb, present in exhaled droplets, is inhaled into the lungs in which the bacteria are taken up by alveolar macrophages. Inside macrophages, mycobacteria manipulate their environment to render the Mycobacterium-containing vacuole (MCV) permissive for their survival and replication.

Mtb and other pathogenic mycobacteria induce damage at the MCV membrane to escape into the cytosol, a step that precedes the egress of the bacteria and their dissemination to neighboring cells. The bacterial translocation into the cytosol depends on the secretion system ESX-1 and the secreted pore-forming peptides ESAT-6 & CFP-10.

The ability of Mtb to infect and persist in host cells is, amongst others, due to its unique cell wall that contains complex outer cell wall lipids. Inhibition of cell wall lipid synthesis can have substantial effects on the outcome of the infection, resulting in severe attenuation and a retention of the bacteria in phago-lysosomes.

Recently, it was shown ESAT-6 acts in concert with phthiocerol dimycocerosate (PDIM), a complex mycobacterial cell wall lipid that is released into host membranes upon infection. It is largely unknown if besides PDIM, other components of the mycobacterial cell wall are involved in phagosomal escape.

This project seeks to unravel the function of cell wall components in phagosomal escape of mycobacteria using the Dictyostelium discoideum / M. marinum infection model. Technical tools to address this question include combinations of live-cell and high-resolution imaging as well as lipidomics.