Mycobacterial cell wall deficiency and its role in the persistence of tuberculosis

Samenvatting

Persistence of Mycobacterium tuberculosis can lead to reactivation of the deadly disease tuberculosis over prolonged periods of time. There are currently no efficient treatments for persistency as the physical state and survival mechanisms of the bacteria in the host are largely unknown. Recent evidence has spurred renewed interest in the concept that persistency could involve cell wall-deficient cells, which are formed after exposure of walled bacteria to high levels of lysozyme in the host. We have obtained compelling evidence that the tuberculosis model organism Mycobacterium marinum can proliferate in a cell wall-deficient state after enzymatic removal of the cell wall. Such wall-deficient cells become insensitive for widely used tuberculosis antibiotics such as isoniazid and ethambutol. As the immune system mainly recognizes cell wall-associated molecules, the formation of wall-deficient variants would enable the pathogen to escape from the immune response. Altogether, the formation of cell wall-deficient cells should be considered a plausible cause for persistency. In this proposal, we will compare both the physiology and morphology of cell wall-deficient cells to isolated persisters of M. marinum. By combining an innovative labelling approach based on two fluorescent reporters with electron cryotomography, we will be able to localize the formation of cell wall-deficient cells in vivo and obtain unprecedented insight in the morphology of these cells. Furthermore, we will study the molecular basis underlying cell wall deficiency and its involvement in persistency. Ultimately, it is likely that our research can guide the development of efficient new drugs to combat this devastating disease.

Kenmerken

Projectnummer

OCENW.KLEIN.039

Hoofdaanvrager

Dr. D. Claessen

Verbonden aan

Universiteit Leiden, Faculteit der Wiskunde en Natuurwetenschappen, Institute of Biology Leiden - IBL

Looptijd

01/05/2019 tot 30/04/2023