Pathogenesis of tuberculosis

Led by Oana Dumitrescu (MCU-PH) and Florence Ader (PU-PH, CIRI Team LegioPath), co-founders of the Lyon TB study group, with contribution of Elisabeth Hodille (PH) and Charlotte Genestet (Post-doc).

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) complex remains a deadly infectious disease worldwide (about 10 million of new TB cases per year leading to 4000 daily deaths). Europe is a considered to be a low prevalence area for TB (3% of the worldwide cases); however, TB remains a threat to public health especially among precarious populations and migrants, turning into a major concern in the context of COVID-19 crisis. TB standard treatment is long and poorly tolerated, early interruption leading to disease relapse. There is urgent need to detect patients at risk for treatment failure and to monitor treatment efficacy. We therefore developed a translational research program, in tight interaction with the Infectious Diseases Department of Lyon University Hospital (Hospices Civils de Lyon), to explore factors related to TB outcome. This project is structured around two axes:

1. We explore the impact of microbial factors on the diverse TB clinical presentations and outcomes. Though Mtb was previously considered genetically monomorphic, we and others have revealed, in studies based on Next Generation Sequencing (NGS), the presence of micro-diversity in Mtb clinical isolates: within hosts, minor variants coexist rather than a clonal colony. We showed the involvement of initial Mtb micro-diversity in antibiotic tolerance and intra-macrophagic persistence. Moreover, we observed that Mtb micro-diversity within patient isolates is strongly correlated with TB-associated severity scores. Currently we aim to decipher the role and the impact in TB presentation of the microbial determinants identified in our previous studies.
2. Through the PRIM-TB project (ANR funded) we will focus on the host factors, to explore the complex interplay between the host’s immune effectors over the course of TB disease management. We aim to identify or validate immune response biomarkers of disease progression and treatment efficacy in active TB-treated patients by using peripheral blood spectral cytometry, transcriptomics and proteomics. For this project we collaborate with Jonathan Hoffmann (Fondation Mérieux, Lyon).

Recent publications: