Morphological switch of atypical mycobacteria - impact on virulence and antibiotic resistance

Infections due to atypical mycobacteria are increasing worldwide.

They mostly affect patients with immunodeficiencies or lung disorders and often result in a chronic pulmonary disease with increased mortality risks.

Due to the high antibiotic resistance of these bacteria, current treatments require multi-drug therapies (>12months) that show toxicity and poor efficacy, while potentially contributing to emergence of drug tolerance and resistance.Mycobacterium avium accounts for most infections by atypical mycobacteria.

Interestingly, M. avium can reversibly change between virulent and avirulent forms, morphologically distinct when grown on agar plates. Importantly, these two forms also differ in antibiotic resistance.

The factors controlling this reversible switch are currently unknown as well as how this switch mechanistically affects host immune defenses, which we plan to elucidate in this project.

A combination of transposon mutagenesis, RNA sequencing, mass spectrometry, as well as genetically modified mouse strains will be employed to uncover these biological processes of great interest, as they could be targeted for drug design or host-directed therapy.Most of the research on mycobacterial virulence has focused on M. tuberculosis, leaving the field of atypical mycobacteria far behind.

As infections by these bacteria are rising, increasing our knowledge on their biology and pathogenesis is crucial, and our work promises to make significant contributions to this field.