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:
- 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.
- 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:
Zein-Eddine R, Hak F, Le Meur A, Genestet C, Dumitrescu O, Guyeux C, Senelle G, Sola C, Refrégier G. The paradoxes of Mycobacterium tuberculosis molecular evolution and consequences for the inference of tuberculosis emergence date. Tuberculosis (Edinb). 2023 Dec;143S:102378. doi: 10.1016/j.tube.2023.102378. Epub 2023 Nov 25. PMID: 38012921
Genestet C, Refrégier G, Hodille E, Zein-Eddine R, Le Meur A, Hak F, Barbry A, Westeel E, Berland JL, Engelmann A, Verdier I, Lina G, Ader F, Dray S, Jacob L, Massol F, Venner S, Dumitrescu O; Lyon TB study group. Mycobacterium tuberculosis genetic features associated with pulmonary tuberculosis severity. Int J Infect Dis. 2022 Dec;125:74-83. doi: 10.1016/j.ijid.2022.10.026. Epub 2022 Oct 21. PMID: 36273524
Genestet C, Baffert Y, Vallée M, Bernard A, Benito Y, Lina G, Hodille E, Dumitrescu O; Lyon TB Study Group. Development, Evaluation, and Implementation of a House-Made Targeted Next-Generation Sequencing Spoligotyping in a French Laboratory. Int J Mol Sci. 2022 Sep 25;23(19):11302. doi: 10.3390/ijms231911302. PMID: 36232601; PMCID: PMC9569608
Bahuaud O, Genestet C, Hoffmann J, Dumitrescu O, Ader F. Opti-4TB: A protocol for a prospective cohort study evaluating the performance of new biomarkers for active tuberculosis outcome prediction. Front Med (Lausanne). 2022 Sep 14;9:998972. doi: 10.3389/fmed.2022.998972. PMID: 36186786; PMCID: PMC9515406
Genestet C, Perdigão J, Herranz M, Maus SR, Berland JL, Chiner-Oms Á, Comas I, Muñoz P, Portugal I, Dumitrescu O, Pérez-Lago L, García de Viedma D. Expanded tracking of a Beijing Mycobacterium tuberculosis strain involved in an outbreak in France. Travel Med Infect Dis. 2021 Nov-Dec;44:102167. doi: 10.1016/j.tmaid.2021.102167. Epub 2021 Sep 17. PMID: 34543757
Genestet C, Hodille E, Barbry A, Berland JL, Hoffmann J, Westeel E, Bastian F, Guichardant M, Venner S, Lina G, Ginevra C, Ader F, Goutelle S, Dumitrescu O. Rifampicin exposure reveals within-host Mycobacterium tuberculosis diversity in patients with delayed culture conversion. PLoS Pathog. 2021 Jun 24;17(6):e1009643. doi: 10.1371/journal.ppat.1009643. PMID: 34166469; PMCID: PMC8224949.
Abascal E, Genestet C, Valera A, Herranz M, Martinez-Lirola M, Muñoz P, Dumitrescu O, García de Viedma D. Assessment of closely related Mycobacterium tuberculosis variants with different transmission success and in vitro infection dynamics. Sci Rep. 2021 May 26;11(1):11041. doi: 10.1038/s41598-021-90568-x. PMID: 34040136; PMCID: PMC8155013
Genestet C, Hodille E, Berland J-L, Ginevra C, Bryant JE, Ader F, Lina G, Dumitrescu O, Lyon TB Study Group. 2020. Whole-genome sequencing in drug susceptibility testing of Mycobacterium tuberculosis in routine practice in Lyon, France. Int J Antimicrob Agents 55:105912. doi:10.1016/j.ijantimicag.2020.105912
Genestet C, Paret R, Pichat C, Berland J-L, Jacomo V, Carret G, Fredenucci I, Hodille E, Rasigade J-P, Boisset S, Carricajo A, Lina G, Ronnaux-Baron A-S, Mornex J-F, Grando J, Sénéchal A, Ader F, Dumitrescu O, Lyon TB study group. 2020. Routine survey of Mycobacterium tuberculosis isolates reveals nosocomial transmission. Eur Respir J 55. doi:10.1183/13993003.01888-2019
Genestet C, Tatai C, Berland J-L, Claude J-B, Westeel E, Hodille E, Fredenucci I, Rasigade J-P, Ponsoda M, Jacomo V, Vachée A, Gaudart A, Gaillard J-L, Roux A-L, Ader F, Tararbit K, Terpant G, Bryant JE, Lina G, Dumitrescu O, on behalf of the Lyon TB Study Group. 2019. Prospective Whole-Genome Sequencing in Tuberculosis Outbreak Investigation, France, 2017–2018. Emerging Infectious Diseases 25:589–592. doi:10.3201/eid2503.181124
Genestet C, Ader F, Pichat C, Lina G, Dumitrescu O, Goutelle S, Lyon TB study group. 2017. Combined Antibacterial Effect of Isoniazid and Rifampicin on Four Mycobacterium tuberculosis Strains: in Vitro Experiments and Response-Surface Modeling. Antimicrob Agents Chemother. doi:10.1128/AAC.01413-17