The role of the mycobacterial proteasome on acid adaptation and chronicity in Mycobacterium tuberculosis infection

• Applicant: Dr. Moritz Kayser
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Clinical Infectiology and Tropical Medicine
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 532589712

Tuberculosis (TB) is a chronic bacterial infection caused by Mycobacterium tuberculosis (Mtb), which primarily affects the lungs of infected patients. TB is still a leading cause of death worldwide, especially in developing economies. However, due to human migration and other factors, TB is also again becoming more frequent in western Europe. There is no effective vaccine against TB for adults and treatment of the infection requires multiple antibiotics and several months and has significant side-effects. On top of that, the rate of drug resistance in Mtb continues to increase dramatically. Further research into the basic biology of Mtb is essential to developing new and better antibiotics. Mtb infects humans through inhaled droplets and can survive and grow inside alveolar macrophages, the most common type of white blood cell in the lung, although these cells would normally eat and kill bacteria through acidity and other means. Mtb is also one of very few bacteria that like humans possess a proteasome, a cell structure that degrades proteins, although of a much simpler type. A CRISPR screen by the Ehrt lab showed that Mtb needs its proteasome to survive in acid conditions, like the ones it encounters in macrophages. In this project, we want to find out whether and how the proteasome helps Mtb to survive in acid conditions. We also want to find out whether Mtb needs the proteasomes ability to dismantle proteins to survive, or some other not yet known function. Additionally, we want to find out how different functions of the proteasome affect Mtbs ability to infect and survive in different sorts of macrophages. In doing so, we hope to find out whether the Mtb proteasome might be a target for future antibiotic therapies.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Dr. Sabine Ehrt