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Team « Research on Mycobacteria and Bordetella »

Our projects are focused on two major bacterial respiratory pathogens: Mycobacteria and Bordetella.

Today, respiratory infections, many of which are caused by pathogenic bacteria, are among the world’s most successful killers.

Tuberculosis (TB) is the cause of approximately 1.8 million annual deaths. Pertussis, the existence of which had almost been forgotten, shows a dramatic global re-emergence, including in high-vaccine coverage countries.

The choice of working in parallel on these two bacterial models is motivated by the fact that whereas both bacteria infect the human respiratory tract, they follow extremely different strategies that we believe are interesting to compare. For both infections, vaccines are available but the re-emergence of both diseases indicates that there is a need for improvement. Moreover, while antibiotic resistance of B. pertussis is currently not a concern, the global spread of multidrug resistant TB is a major problem.

The objectives of the team are :

(i) to study the molecular mechanisms of pathogenicity of B. pertussis and M. tuberculosis pathogen families,

(ii) to analyse the genome evolution of M. tuberculosis and the genetic regulation of the two pathogens,

(iii) to use this knowledge to develop novel approaches to design better vaccines, new therapeutics and new methods for molecular diagnostics and molecular surveillance, which are urgently needed to fight against these deadly scourges.

Thus, our research is a continuum from a continuous acquisition of basic knowledge to the development of clinical applications and investigations. These ambitious objectives are led with the help of collaborations with many academic French collaborators, including within the CIIL, and international laboratories, in the framework of multiple ANR and EU programmes, and with very active private partners participating to the clinical and industrial development of our discoveries.

Our youngest team members: from left to right, Fethi Khiter (PhD), Violaine Dubois (postdoc), Astrid Lenne-Delmotte (postdoc), Oriane Riviere (PhD), Gauthier Roy (PhD), Laura Leprevost (PhD), Kamel Djaout (postdoc) and Elena Santiesteban (postdoc).

Main projects of the team RMB

Molecular mechanisms of pathogenicity of B. pertussis and M. tuberculosis pathogen families

Handling of copper by a host-restricted pathogen.

A recent project in the laboratory aims at elucidating the homeostasis of copper, an important player at the host-pathogen interface, in Bordetella pertussis. As a strict aerobe, B. pertussis needs copper notably for its heme-copper cytochrome oxidases. However, copper is also toxic and is notably used by phagocytic cells to kill bacteria. We have discovered that B. pertussis has shed most of its defenses against copper and conversely has acquired a specific copper acquisition system which is tightly regulated. It also produces a new type of natural product that binds copper and most likely participates in its homeostasis. (contact: francoise.jacobibl.cnrsfr)

Mechanisms of intracellular degradation of B. pertussis

Xenophagy represents a highly conserved defense mechanism of eukaryotic cells involved in the clearance of invading pathogens. During this complex process, intracellular micro-organisms are targeted to the degradative lysosomal compartment. A non-canonical autophagic pathway through LC3-associated phagocytosis (LAP) also contributes to immune regulation and inflammatory responses.

Once therespiratory pathogen B. pertussis is inhaled, it will encounter phagocytic cells which represent a first line of defense against the infection. Among them, alveolar macrophages play a key role in protection. A knowledge gap exists on the involvement of autophagy and/or LAP in the intracellular clearance of B. pertussis and its impact on innate immune responses. We established a novel partnership with Dr. Ghaffar Muharram (MCPI team, CIIL) to tackle this question. (contact: nathalie.mielcarekinsermfr; carine.rouanet@ibl.cnrs.fr)

Implication of protein-protein interactions in mycobacterial pathogenesis

Deciphering the Protein-Protein Interactions (PPI) in pathogenic bacteria may help to understand the physiology of the cell and to elucidate host-pathogen interactions, in which proteins play crucial roles. In addition, the study of PPI may facilitate the discovery of protein functions by the ‘guilty by association’ principle.

As PPI are key factors in Mycobacterium tuberculosis physiology and virulence, we are particularly interested in deciphering PPI network in mycobacteria at the cell wall and the membrane level. For example, mycolic acid biosynthesis, which is the target several antiTB drugs, relies on specialized and interconnected protein complexes. Hence, the identification and the characterization of PPI may represent an attractive approach for the development of new drugs and/or peptidomimetics. In addition, deciphering the PPI network of M. tuberculosis will lead to the identification of critical steps required for mycobacterial infection and will allow a better understanding of TB pathogenesis. (contact: romain.veyron-churletibl.cnrsfr)

Genetic regulation and genome evolution

Bordetellae’s gene expression regulation

The Bordetellae, encompassing the human pathogen B. pertussis and the veterinary pathogen B. bronchiseptica, produce an arsenal of virulence factors such as adhesins and toxins, that allow the bacteria to transmit, infect and colonize the respiratory tract of the host. These bacteria regulate their virulence factor expressions according to environmental conditions. Hence, these species have a complementary set of capabilities that is regulated in an inverse fashion. In the virulence phase the virulence-activated genes or vags are transcribed and their expression is regulated by a two-component system BvgAS. In the a-virulence phase, the vags are not expressed but instead, the virulence-repressed genes or vrgs are expressed. The expression of the vrgs is regulated by another two-component system RisA/K and by the action of BvgR, a c-di-GMP phosphodiesterase. Using molecular biology and omics’s technologies, our goal is to define the regulation network and the mode of regulation involving the BvgASR and the RisAK systems. Additionally, B. pertussis encodes for up to 16 different two-component systems arguing on the extreme complexity of the Bordetella gene expression biology. (contact: loic.coutteinsermfr)

Evolutionary history and factors driving the spread of tuberculosis

Mycobacterium tuberculosis is the deadliest bacterial infectious agent globally and the first contributor to antimicrobial mortality. Using comparative genomics and pathophysiological approaches applied to strain lineages with different epidemic and/or antibiotic resistance profiles, we aim at identifying the factors that have contributed to its emergence and its exceptional evolutionary success, including in multidrug-resistant (MDR) forms.

This work has led to the discovery of exceptional ancestral branches of tubercle bacilli in East Africa, which was the foundation for the identification of novel molecular mechanisms of virulence/persistence of the pathogen in the host. We also used/use whole genome sequencing to reveal the longitudinal spread of epidemic MDR clones, and to expand knowledge on drug resistance associated mutations, which is necessary for maximizing the accuracy of novel molecular diagnostic tools. (contact: philip.supplyibl.cnrsfr)

Translational research

BPZE1 vaccine against pertussis

Decades of research on the molecular pathogenesis of pertussis have allowed us to develop a novel, live attenuated nasal pertussis vaccine called BPZE1. In contrast to the currently available vaccines, this vaccine protects both against pertussis disease and infection by the causative agent Bordetella pertussis, as assessed in mice and non-human primates. It is now in clinical development and has successfully completed two phases I and two phases II clinical trials. These trials have shown that the vaccine is safe in humans, able to transiently colonize the human respiratory tract, to induce both humoral and T cell responses and to prevent subsequent colonization by a second dose of the vaccine strain. In addition to continuing its clinical development, current research focuses on using the vaccine strain for the presentation of heterologous antigens to the respiratory mucosal immune system. (contact: camille.lochtinsermfr; nathalie.mielcarekinsermfr)

Deep sequencing for culture-free diagnosis of drug resistance in mycobacteria (Deeplex Myc-TB and Deeplex Myc-Lep)

Less than 40% of the estimated 460,000 new TB cases with rifampicin resistance or multidrug-resistance occurring each year are diagnosed and treated, reflecting important limitations of conventional phenotypic and molecular tests. By building on the impressive progress of next-generation sequencing (NGS) technologies and the knowledge gained on the catalogue of resistance determinants in the M. tuberculosis genome, novel tools for rapid NGS-based, culture-free diagnostics are developed by ©GenoScreen (Lille) with our collaboration. This has led to the development of the Deeplex® Myc-TB kit, based on deep amplicon sequencing for prediction of susceptibility or resistance to 13 anti-tuberculosis drugs/drug classes, directly applicable on clinical samples. As a unique feature compared to other commercial molecular tests, this assay also includes genotypic detection of recently re-defined extensively drug resistant (XDR) tuberculosis. It is used by the WHO for surveillance of drug resistant TB and in >25 countries, and is being evaluated in several MDR-TB diagnostic trials, e.g. in Africa in the DIAMA H2020 EDCTP project. A similar test is being developed for culture-free diagnosis of the agent of leprosy, M. leprae, which is unculturable in vitro. (contact: philip.supplyibl.cnrsfr)

INFLAMMAVAX (Anti-inflammatory benefits of BPZE1)

With advancing age, the immune system undergoes a dynamic change characterized by the coexistence of a weaker immune response to newly encountered pathogens or vaccine antigens, and a systemic inflammatory state that is involved in the development of cardiovascular disease, metabolic disorders and cancer in the elderly. During the development of the attenuated live pertussis vaccine (BPZE1) in our laboratory, we have observed non-specific anti-inflammatory properties that protect against morbidity and mortality associated with inflammation induced by heterologous viral or bacterial infections, as well as against non-infectious inflammatory disorders, such as allergic asthma. In our project, we plan to understand the molecular mechanisms behind these protective anti-inflammatory effects. The basic knowledge resulting from our project will open new avenues for the prevention of chronic inflammation, the common denominator of all age-related diseases. In the long term, our study may thus lead to novel anti-inflammatory therapies promoting healthy longevity. (contact : stephane.cauchiibl.cnrsfr)

Small Molecules Aborting Resistance against Tuberculosis (SMARt-TB)

Alarmingly, multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis have now spread worldwide. Some key antituberculosis antibiotics are prodrugs, for which resistance mechanisms are mainly driven by mutations in the bacterial enzymatic pathway required for their bioactivation. We are developing molecules that stimulates alternative prodrug activation pathway called Small Molecules Aborting Resistance (SMARt).

SMARt molecules aborting ethionamide resistance have been discovered in collaboration with team U1177 (ANR-IPL-Région HdF). First-in human study was initiated by Bioversys and GSK in 2020 with a molecule reverting Ethionamide resistance. A second family of compound aborting Pretomanid and Delamanid resistance is under evaluation with the support of ANR and SATT-Nord. The bioactivation of fluoroquinolone derivatives is also studied in collaboration with the team of Alexandra Aubry (Paris-CIMI), supported by the ANR project Detonator. (Contact: alain.baulardinsermfr )

Our team coordinates the “Mustart” project recently funded by the French initiative “Investments for the Future”(PIA3). Mustart associates 9 French academic experts to develop multifaceted regimens targeting the most coriaceous TB bacilli in their peculiar physiological niches, and to identify biomarkers of the treatment progress. (Contact: alain.baulardinsermfr )

INTERNSHIP

For all internship applications, please send your request directly to the group leader of the research area that you are interested in :
1- Bacteria, Antibiotics & Immunity : Contact
2- Biology of Apicomplex Parasites : Contact
3- Cellular Microbiology & Physics of Infection : Contact
4- Chemical Biology of Antibiotics : Contact
5- Chemical Biology of Flatworms : Contact
6- Chemogenomics of Intracellular Mycobacteria : Contact
7- Ecology & Physiopathology of Intestinal Protozoa : Contact
8- Influenza, Immunity & Metabolism : Contact
9- Lung Immunity : Contact
10- Molecular & Cellular Virology : Contact
11- Opportunistic Infections, Immunity, Environment & Lung Diseases: Contact
12- Plague & Yersinia pestis : Contact
13- Research on Mycobacteria and Bordetella: Contact
14- Tropical Biomes & Immuno-Pathophysiology : Contact


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