Mycobacterial cell wall-deficiency and its role in the persistence of tuberculosis
What is the role of cell wall-deficiency in the persistence of tuberculosis?
Tuberculosis is one of the deadliest infectious diseases, which annually kills more than 1.6 million people worldwide. However, despite decades of research, there is still no efficient treatment for latent infections. One of the fundamental problems in such latent infections is the formation of so-called persister cells, which are largely invisible for the immune system and reside in the host in an inactive state. Classically, persister cells are difficult to cultivate, which leads to many unanswered questions about their morphology, physiology and mechanisms of survival. A crucial target for bacterial recognition by the host immune system is the cell wall, and transient loss of this structure would enable cells to escape recognition by the host. In this wall-deficient state, the cells become insensitive towards antibiotics that target the cell wall, even though these drugs are commonly used to treat tuberculosis infections. Given that pathogenic bacteria are exposed to large amounts of lysozyme produced by phagocytic immune cells of the host, the formation of cell wall-deficient cells could be an important factor to explain persistency. In this project, we will perform a detailed high-resolution structural and molecular analysis of cell wall-deficient cells inside the host and compare them to persisters of the pathogen. This will not only shed unprecedented insight into latent tuberculosis infections, but also provide important new leads for the development of drugs combating recurring infectious diseases more generally.