Research on Mycobacteria and Bordetella

INSERM U1019 – CNRS UMR9017 – Lille University – CHU Lille – Institut Pasteur de Lille

CIIL recherche pasteur lille

Presentation

The activities of our team are focused on two bacterial pathogens of the respiratory tract, Mycobacterium tuberculosis and Bordetella pertussis, responsible for tuberculosis and pertussis, respectively. The re-emergence of these two diseases highlights the need for improving existing control tools. Furthermore, the global spread of multidrug-resistant tuberculosis adds to these major public health problems. Our objectives are (i) to study the molecular mechanisms of the pathogenicity of B. pertussis and of M. tuberculosis, (ii) to analyze the genomic evolution of M. tuberculosis and the genetic regulation of the two pathogens, and (iii) to use this knowledge to develop novel approaches for designing better vaccines, improved therapies, diagnostic methods and molecular monitoring, urgently needed to combat these deadly scourges. These ambitious objectives are achieved through collaborations with numerous French and international academic laboratories and with private partners participating in the clinical and industrial development of our discoveries.

Highlights

  • New concept of antibiotic therapy. The studies on the control of transcriptional regulation in M. tuberculosis, in particular on the role of the transcriptional repressors EthR and EthR2 in the bioactivation pathway of ethionamide, made it possible to discover a new class of molecules called “SMARt” and allowing a reversion of resistance in M. tuberculosis to ethionamide, while increasing its antibiotic effect. A phase 1 clinical study has just started in collaboration with GSK and BioVersys.
  • Diagnosis of latent tuberculosis. A new diagnostic test for latent tuberculosis, based on the HBHA adhesin discovered and studied in the laboratory, is currently in development in partnership with Lionex and the Université Libre de Bruxelles.
  • New molecular diagnostic and surveillance tests for multidrug-resistant tuberculosis and leprosy. Research on the genomics and evolution of M. tuberculosis has enabled the creation of diagnostic tests based on next generation sequencing (NGS) by Genoscreen in collaboration with our laboratory. These tests, one of which is already used by WHO for monitoring multidrug resistance, are being clinically evaluated in two H2020 projects involving European and African partners.
  • New vaccines against pertussis and other diseases. The studies on B. pertussis virulence factors and bacterial pathogenesis have made it possible to construct a genetically attenuated strain (BPZE1) capable of mimicking a natural infection without inducing pathology. A license and collaboration agreement with ILIAD Biotechnologies now allows the further development of this vaccine, which is currently in clinical phase 2 in the United States. The use of BPZE1 as an anti-inflammatory agent and as a recombinant nasal vaccine against various diseases, including Covid-19, is being investigated with funding from the Ministry of Research.

Transversal project

ERA4TB (European Regimen Accelerator for Tuberculosis) is an international consortium aiming to accelerate the development of new treatment regimens for tuberculosis.

Tuberculosis is the leading cause of death from infectious disease worldwide, and the continued development of antibiotic resistance makes the disease very difficult to treat. ERA4TB is a public-private partnership designed to revolutionize anti-tuberculosis treatment. To be effective, current anti-tuberculosis treatments require taking several antibiotics over a minimum of 6 months and up to two years or more. ERA4TB’s goal is to replace these anti-tuberculosis treatments with ideally shorter therapies, based on modern, synergistic and safe combinations of new antibiotics. ERA4TB is one of the largest partnerships ever funded by IMI (Innovative Medicine Initiative -EU), intended to parallel all the steps to quickly identify the best combinations of antibiotics.

More than 30 universities and private partners from 13 countries are participating in this project. Among them, four research teams from the Institut Pasteur de Lille, including 3 from the CIIL, will play a decisive role in the evaluation of drug combinations, by studying their mode of action and their pharmacokinetics, key parameters to identify the best regimens. therapies for tuberculosis patients.

Members

Nathalie MIELCAREK
DR2 Inserm, group leader
ORCID number : 0000-0002-5968-9442

Camille LOCHT
DRE Inserm
ORCID number : 0000-0001-7295-7336

Alain BAULARD
DR2 Inserm
ORCID number : 0000-0002-0150-5241

Françoise JACOB-DUBUISSON
DR1 CNRS
ORCID number : 0000-0002-5102-1704

Philip SUPPLY
DR1 CNRS
ORCID number : 0000-0003-3690-3853

Rudy ANTOINE
CRCN Inserm
ORCID number : 0000-0002-7369-0626

Loïc COUTTE
CRCN Inserm
ORCID number : 0000-0002-8626-8109

Stéphane CAUCHI
CRCN CNRS
ORCID number : 0000-0003-0737-9300

Carine ROUANET
CR IPL
ORCID number : 0000-0001-9105-1855

Romain VEYRON-CHURLET
CRCN CNRS

Nicolas BLONDIAUX
MCU-PH CH Tourcoing

Christine DEMANCHE
MCU CHU Lille
ORCID number : 0000-0002-5425-8010

Olivier GAILLOT
MCU-PH CHU Lille
ORCID number : 0000-0001-8036-0142

Patrice NORDMANN
Univ Fribourg, Suisse

Dominique RAZE
IR2 Inserm

Anne-Sophie DEBRIE
IE IPL

Sophie LECHER
TS IPL

Emmanuelle PETIT
TCN Inserm

Stéphanie SLUPEK
TCN IPL

Thomas BELCHER
Post-doc

Kamel DJAOUT
Post-doc

Violaine DUBOIS
Post-doc

Violaine DUBOIS
Post-doc

Astrid LENNE
Post-doc

Alex RIVERA
Post-doc

Jonathan CHATAGNON
IE

Laura LEPREVOST
PhD student

Fethi KHITER
PhD student

Gauthier ROY
PhD student

Publications

Blondiaux N, Moune M, Desroses M, Frita R, Flipo M, Mathys V, Soetaert K, Kiass M, Delorme V, Djaout K, Trebosc V, Kemmer C, Wintjens R, Wohlkönig A, Antoine R, Huot L, Hot D, Coscolla M, Feldmann J, Gagneux S, Locht C, Brodin P, Gitzinger M, Déprez B, Willand N, Baulard AR.
Reversion of antibiotic resistance in Mycobacterium tuberculosis by spiroisoxazoline SMARt-420.
Science. 2017 355(6330):1206-1211.

Jacob-Dubuisson F, Mechaly A, Betton JM, Antoine R.
Structural insights into the signalling mechanisms of two-component systems.
Nat Rev Microbiol. 2018 16(10):585-593.

Jahnmatz M, Richert L, Al-Tawil N, Storsaeter J, Colin C, Bauduin C, Thalen M, Solovay K, Rubin K, Mielcarek N, Thorstensson R, Locht C ; BPZE1 study team.
Safety and immunogenicity of the live attenuated intranasal pertussis vaccine BPZE1: a phase 1b, double-blind, randomised, placebo-controlled dose-escalation study.
Lancet Infect Dis. 2020 20(11):1290-1301. Erratum in: Lancet Infect Dis. 2020 20(9):e215.

Jouet A, Gaudin C, Badalato N, Allix-Béguec C, Duthoy S, Ferré A, Diels M, Laurent Y, Contreras S, Feuerriegel S, Niemann S, André E, Kaswa MK, Tagliani E, Cabibbe A, Mathys V, Cirillo D, de Jong BC, Rigouts L, Supply P.
Deep amplicon sequencing for culture-free prediction of susceptibility or resistance to 13 anti-tuberculous drugs.
Eur Respir J. 2020 17:2002338. 

Ngabonziza JCS, Loiseau C, Marceau M, Jouet A, Menardo F, Tzfadia O, Antoine R, Niyigena EB, Mulders W, Fissette K, Diels M, Gaudin C, Duthoy S, Ssengooba W, André E, Kaswa MK, Habimana YM, Brites D, Affolabi D, Mazarati JB, de Jong BC, Rigouts L, Gagneux S, Meehan CJ, Supply P.
A sister lineage of the Mycobacterium tuberculosis complex discovered in the African Great Lakes region.
Nat Commun. 2020 9;11(1):2917.


Keywords

Tuberculosis ; Pertussis ; Virulence ; Génomics ; Diagnostic ; Vaccines ; Drugs resistance

Team contact

Nathalie Mielcarek
Group leader

nathalie.mielcarek@inserm.fr
03 20 87 10 28