The world
of the infinitely small

OUR PREVIOUS TEAMS HIGHLIGHTED

The Molecular & Cellular Virology (MCV) team is dedicated to the study of positive-strand RNA viruses. Our main objective is to better understand how these viruses interact with their host at the cellular and molecular level. Our viral models are hepatitis C virus (HCV), hepatitis E virus (HEV) and coronaviruses. For more than 28 years, the team has been studying the HCV life cycle and it has largely contributed to the understanding of several steps of entry, replication and assembly of this virus. In 2013-2014, after the development of potent antivirals against HCV, we started to work on other viral models, including HEV and highly pathogenic coronaviruses like MERS-CoV and, since 2020, SARS-CoV-2. These viruses are emerging in human populations and can be life threatening. Our objective is to better understand the life cycle of these viruses and identify novel antiviral compounds.

Jean Dubuisson : Head of team

Learn more about the team : HERE

Molecular and Cellular Aspects of the Hepatitis E Virus lifecycle : Laurence COCQUEREL

Hepatitis E virus (HEV) is the major cause of acute viral hepatitis worldwide. Although infection with HEV is usually self-resolving, it can cause up to 30% mortality in pregnant women and leads to a chronic infection in immunocompromised patients. There is no specific treatment nor universal vaccine to fight against this virus. HEV is a quasi-enveloped, positive-sense RNA virus expressing three open reading frames (ORFs): ORF1 that encodes the ORF1 viral replicase, ORF2 that encodes the ORF2 viral capsid protein and ORF3 that encodes a small protein involved in virion morphogenesis and egress. Due to poor replication in cell culture, many data are missing on the different steps of the HEV lifecycle.

Few years ago, we developed an efficient cell culture system for HEV which allows for studying the molecular and cellular mechanisms of the HEV lifecycle. This model notably enabled the pioneering demonstration that, during its lifecycle, HEV produces at least 3 forms of the ORF2 capsid protein: infectious ORF2 (ORF2i), glycosylated ORF2 (ORF2g), and cleaved ORF2 (ORF2c). These ORF2 forms perform distinct functions in the HEV lifecycle. The ORF2i protein is the structural component of infectious particles whereas the ORF2g/c proteins are not associated with infectious material but likely act as a humoral immune decoy that inhibits antibody-mediated neutralization. The ORF2g/c proteins are secreted in large amounts in culture supernatant and are the most abundant antigens detected in patient sera.

Very recently, we deciphered the molecular determinants of ORF2 multifunctionality. We identified an arginine-rich motif (ARM) located in the ORF2 N-terminal region that controls the subcellular localization, the fate and functions of ORF2 forms. It also promotes ORF2-host cell interactions. Our observations highlighted the ORF2 ARM as a unique central regulator of ORF2 addressing that finely controls the HEV lifecycle.

In another study, we generated monoclonal antibodies that specifically recognize the particle-associated ORF2i form, and antibodies that recognize the different ORF2 isoforms. We used them in confocal and electron microscopy approaches to probe infectious particles and viral factories in HEV-producing cells. We identified an unprecedented HEV-induced membrane network containing tubular and vesicular structures that were enriched in ORF2 and ORF3 viral proteins. Moreover, extensive colocalization analyses of viral proteins with subcellular markers demonstrated that these structures were derived from the endocytic recycling compartment (ERC).

In addition, in a study aiming at characterizing the ORF1 replicase and using the RNAscope technology, we revealed that the ORF1 protein and genomic RNA were also enriched in the ERC-derived subcellular structures, indicating that cellular ERC serves a viral factory for HEV. Therefore, our studies demonstrated that HEV hijacks the ERC during its lifecycle and forms a membrane network of vesicular and tubular structures that might be the hallmark of HEV infection.

Morphogenesis of coronaviruses : Sandrine BELOUZARD

Coronaviruses nucleocapsid is surrounded by a host-cell derived lipidic bilayer in which 3 viral proteins are anchored, forming the viral envelope. The well-known spike proteins form protrusion at the viral giving its particular shape to the virus family. The spike protein (S) is responsible for the entry of the virus in the host cell therefore being the major factor of viral tropism. The membrane protein (M), the most abundant component of the viral envelope with the small envelope protein E is involved in viral assembly. The M protein consists of a small, N-glycosylated terminal ectodomain, followed by three transmembrane segments and a large C-terminal endodomain. Indeed molecular interactions have been demonstrated between the M protein and all the structural proteins (E, S and N). Therefore, the M protein is considered as the driving force in viral assembly. Coronavirus assembly occurs in the intermediate compartment between the endoplasmic reticulum and the Golgi (ERGIC). However, due to its complexity, the assembly process of coronaviruses remains poorly understood. The formation of new coronavirus virions has two pre-requisites: (1) the localization of all the structural components of the virus to the assembly site and (2) a series of protein-protein interactions (M-M; M- E; M-S; M-N and most probably viral-host protein interactions) to ensure the incorporation of all structural proteins and release of the correctly formed, infectious particles. Since the M protein is the driving force in coronavirus morphogenesis, the main objective of this project is to better understand the assembly mechanism of betacoronaviruses by focusing on the role of the M protein in this process.  More precisely our goal is to identify M region involved in viral morphogenesis and determine their mechanism of action. When expressed individually, the M proteins of most coronaviruses are retained in the Golgi complex. MERS-M and SARS-2-M are retained in the trans-Golgi network. In the C-terminal 20 residues of the MERS-CoV M protein, we identified two signals involved in its intracellular trafficking. Indeed, a first DxE motif is responsible for the ER export of the protein, and a second motif KxGxYR participates in the TGN retention signal of the protein. Mutation of this second motif results in an increase of the trafficking of the protein toward the plasma membrane and inhibits viral assembly.  The KxGxYR motif is highly conserved in betacoronavirus, including SARS-CoV-2 M (RxGxYK). We are currently performing mutagenesis of the SARS-2-M to better characterize its intracellular trafficking. We also aim at identifying cellular factors involved in coronavirus assembly and how the M protein may recruit these factors.

Natural compounds & Antivirals : Karin SERON

Identification of antivirals targeting different steps of viral life cycle could serve as basis for the discovery of novel therapies and might help to better understand viral infectious cycle. Plants have been used for centuries in traditional medicine to cure different kinds of illnesses, and natural products from plant species maintain a strong position in the drug discovery. Even if natural products are not always used directly as medicines, they often remain a source of inspiration for medicinal chemistry. Recently we have focused our research on SARS-CoV-2 antivirals from plant origin. We have screened plant extracts for their antiviral activities against coronaviruses and identified a plant extract, from Côte d’Ivoire (selected by Moussa Bamba, PhD student and Fézan Tra Bi, Université Nangui Abrogoua, Abidjan), with a very high antiviral capacity. Thanks to a collaboration with the pharmacognosy laboratory from the Faculté de Pharmacie de Lille (Pr Sevser Sahpaz and Dr Simon Bordage), the extract was fractionated using a bio-guided fractionation procedure and we were able to identify the active compound, “pheophorbide a”. This compound is a breakdown product of chlorophyll and is a photosensitizer. We have shown that the antiviral activity of pheophorbide is dependent on light activation and induces a rigidification of the viral envelope. This was observed by cryo-electron microscopy (collaboration with Olivier Lambert and Marion Decossas, CBMN UMR 5248, Bordeaux). Pheophorbide is the first described natural antiviral against SARS-CoV-2 with direct photosensitive virucidal activity that holds potential for COVID-19 therapy or disinfection of SARS-CoV-2 contaminated surfaces. New projects are underway to explore the antiviral capacities of plant-derived molecules.

Molecular and cellular mechanisms driving peroxisome alterations in cells infected with hepatitis C virus : Yves ROUILLE

Hepatitis C virus (HCV) is an important human pathogen that infects the liver and frequently establishes a chronic infection, leading to steatosis, fibrosis, cirrhosis and hepatocellular carcinoma over many years. Despite recent advances in HCV treatment, the risk of HCV-induced complications is reduced, but not completely eliminated in patients who have resolved their infection.
The molecular and cellular mechanisms leading to the pathological disorders are not yet well understood. At the cellular level, HCV infection induces morphological and metabolic alterations. A number of cellular factors are recruited by the virus to carry out the different steps of its life cycle and, in particular, the replication of its genomic RNA within induced membrane rearrangements. This recruitment may divert some of the recruited cellular factors from their normal intracellular localization and function, which may interfere with cellular metabolism and thus contribute to the pathogenesis.
A project to identify host cell factors recruited to HCV replication sites led to the identification of ACBD5 (Acyl-CoA-binding domain-containing protein 5). ACBD5 is a peroxisome membrane protein that mediates membrane contact sites to the endoplasmic reticulum (ER) membrane via interaction with VAP-A/B, two ER membrane proteins that are important for HCV infection. Confocal microscopy experiments confirmed the recruitment of peroxisomes in close proximity of HCV replication complexes and also revealed alterations in peroxisome morphology. We are investigating the interplay between HCV and peroxisomes by assessing the function of peroxisomes in HCV replication and characterizing the impact of HCV infection on peroxisome function, with a particular focus on oxidative stress. We expect that this project will reveal molecular and cellular mechanisms induced by HCV to alter cellular metabolism and specifically peroxisome functions, which are known to decline in hepatocytes of chronically infected patients.


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 )


Testimonies

Alix Laffitte, PhD student, and Servane Le Guillouzer, Post-doctoral fellow, in the Plague and Yersinia pestis team, retrace their academic careers and their plans for the future. They will present their research topics. Discover their testimonies!

News or fiction? The plague has been eradicated

The last case in France was in 1945, but has it disappeared?

Since Antiquity, it has killed 200 million people. The trauma in the West was such that it still permeates our vocabulary, whether we are referring to people ("a plague", "a pestilence"), smells (pestilential) or an infernal dilemma ("Choose between plague and cholera"). "In France, after the plague of the ragpickers in Paris in 1920, there was a last case in Corsica in 1945," says Florent Sebbane, head of the Plague and Yersinia pestis laboratory at Inserm.

To learn more --> HERE (source in french)

Plague, believed to be a disease of the past, has never been eradicated. In this 39.6  TV documentary from the Radio Télévision Suisse, you will discover the research carried out by the teams of Dr. Florent Sebbane at the Pasteur Institute of Lille and Dr. Javier Pizarro-Cerda at the Pasteur Institute in Paris on Plague: from deciphering the mechanisms of flea-borne transmission to the development of a vaccine.

Youtube Video: Peste, leptospirose et maladies oubliées : le retour - 36.9°


More details on TBIP team --> HERE

The general objective of the team’s research project is to evaluate the complex nature of immune mechanisms induced during protozoan parasite (co)infections.  In the high endemic areasof the Amazonian ecosystem of the French Guyana concomitant infections by Plasmodium, Leishmania and Toxoplasma cause more chronic asymptomatic disease than acute severe illnesses. Such asymptomatic individuals develop anti-disease immunity and become parasite reservoirs. The workprogram is based on a “one health” strategy capitalizing on the strength and the multidisciplinary expertise of the team members (clinicians working on the field in FG, molecular parasitology, epidemiology and immunology). The specific aims are to: 1) identify immune signatures associate to protection or pathology and 2) investigate how they are modulated by environmental factors and host multi-biome and influence the disease progression in such settings. Data obtained should allow to identify disease phenotype biomarkers and targets for diagnosis, prognosis, prevention and treatment.

The team is composed of two groups: 1) group 1 at the Institute Pasteur of Lille is leaded by S. Pied DR CNRS and 2) group 2 at the University of Guyana and Cayenne Hospital (CHAR) leaded by M. Demar, PU-PH.  The team is linked to the Laboratory of Parasitology–Mycology and several medical units, including the departments of 1) infectious and tropical diseases, 2) dermatology, and 3) several health centers for remote areas of Guiana. Moreover, TBIP has ties with the Clinical Investigation Center (CIC INSERM-CIE 802 leaded by M. Nacher).

Through the weekly episodes, you will discover our different research themes from Lille and French Guyana. For this first week, zoom on Amazonian toxoplasmosis…

Episode 1

Episode 2

Episode 3

Episode 4


Team Bacteria, Antibiotics, and Immunity

Respiratory tract infections represent the third major cause of death worldwide. Among them, bacterial pneumonia (either community- or hospital-acquired) are major causes of morbidity, quality-adjusted life year loss, and mortality in children, adults, and the elderly. Although the discovery of antibiotics to treat bacterial pneumonia was a remarkable achievement in the 20th century, the effectiveness of antibiotics is declining, because of antimicrobial resistance (AMR). The World Health Organization (WHO) estimates that bacterial infections due to AMR will outcompete any cause of death by 2050, meaning that it is crucial to develop new strategies to improve antibacterial treatment.

The team "Bacteria, Antibiotics, and Immunity" studies pathogenic bacteria responsible for pneumonia listed by the WHO as priority targets in the fight against AMR: Streptococcus pneumoniae and Klebsiella pneumoniae. Our studies make use of cell and animal models as well as clinical studies with the GHICL hospitals in Lille to translate findings from bench to bedside. The team especially investigates the immune responses that are triggered by the bacterial infection of the respiratory tract, by the antibiotics during the treatment of such infections and aims to define groundbreaking interventions that increase innate immune defenses. Notably, innate immunity mobilizeq a variety of antibacterial effectors; Emergence of resistance to these immune effectors would be unlikely. The ultimate objective of the team is to combat the emergence of AMR by novel interventions that combine stimulation of innate immune responses and antibiotherapy.

The team currently explore three research axes:

  • Demonstrating the proof-of-concept of aerosol delivery of immune-modulator as an innovative pneumonia treatment
  • Defining the contribution of innate immune effectors in the effectiveness of antibiotic treatment of infections
  • Dissecting the mechanisms involved in the innate IL-17/IL-22 responses to develop immune-boosters of antibiotics

In conclusion, our studies tests and optimizes emerging concepts of immunotherapy of bacterial pneumonia in combination with the standard of care that are antibiotics in order to address the problem of AMR.

More information about the team : HERE

Demonstrate the proof of concept of aerosol delivery of immune-modulator
as an innovative
pneumonia treatment

 

The team coordinates the European project FAIR (https://fair-flagellin.eu) that aims at targeting the innate immune system as an underexploited area of drug discovery for infectious diseases. To this purpose, the FAIR project develops inhaled flagellin as an adjunct therapy in bacterial pneumonia. Flagellin is an agonist of the Toll-like receptor 5 that activates signaling in the respiratory epithelium and thus, protective innate defenses against pneumonia. It has already been shown that flagellin activates local or systemic innate immunity and enhances the therapeutic outcome of pneumonia caused by antibiotic susceptible or resistant S. pneumoniae and K. pneumoniae. We aim at dissecting the mode of action of flagellin during pneumonia treatment. The project also ambitions to setup a first-in-man phase I clinical trial.

Decipher the nature of innate immune effectors contributing to antibiotics efficacy during bacterial pneumonia

Antibiotics are uniquely considered as direct antimicrobial agents, and most efficacy evaluations are based on in vitro assays or immunosuppressed animals. Growing evidence suggests that antibioticsinteract with host innate immunity to provide potent indirect effects which enhance bacterial clearance and may result in more rapid and complete therapeutic effects. The team is characterizing the dynamics of myeloid cell differentiation and functions during the antibiotic treatment of bacterialinfection in mice, in order to identify novel immunomodulatory agents.

Dissect the innate IL-17/IL-22 responses to improve treatment of pneumonia and boost antibiotic effectiveness.

 

The innate lymphocytes that produce the cytokines IL-17 and IL-22 are essential to promote respiratory innate antimicrobial defenses and tissue repair. The team aims at understanding how these responses are induced in the respiratory tract during self-limiting bacterial pneumonia in order to develop innovative interventions.

Our new Post doc
Our new PhD students

Mara Baldry - Postdoctoral researcher Scientific manager of FAIR. Immune corelates of protection to inhaled flagellin as adjunct of antibiotics.

Charlotte Costa - PhD Student. Impact of immunotherapies on the treatment and emergence of antibiotic-resistant pneumonia.

Mélanie Mondemé - PhD Student. Dynamics of myeloid cells during antibiotherapy of pneumonia.

Xing Li - PhD Student. Innate response of human primary respiratory cells to infections and immune-modulators.

Yasmine Zeroual - PhD Student. Modeling of protective innate immunity by Omics analysis.


Chronic respiratory diseases are a major cause of mortality and morbidity. The respiratory tree is located at the interface between environment and host, and as such plays a critical role in the development of the host immune response that can be either beneficial or deleterious. This immune response is one pathway to target, to modify the natural evolution of respiratory diseases.. Among them, the team studies two respiratory diseases, the acute respiratory distress syndrome (ARDS), often of infectious origin, and severe asthma.  Due to strong links with the pneumology and critical care departments of the CHU of Lille, we are very focused on translational research from the bench to the clinic.
In the context of ARDS, a link has been shown between low levels of endocan, a proteoglycan cloned in the lab, and the development of ARDS during septic shock (Gaudet et al, J Crit Care, 2018). This led us to evaluate endocan in a cohort of COVID patients hospitalized in critical care depertment of Foch Hospital (Suresnes). The results have shown that endocan was increased in COVID versus non COVID patients, and that patients developing the more severe ARDS had the lowest levels of endocan between D3 and D5 following tbeir admission in critical care,. These data suggest a predictive role of this molecule in in the development of ARDS in COVID patients (Pascreau et al, Crit care, 2021).
In the context of asthma, this disease remains a major challenge because of the diversity of its clinical phenotypes and biological mechanisms. Severe asthma concerns 5 to 10% of total asthmatics (more than 300 millions people in the world), but generates almost the totality of health costs devoted to this disease. Severe asthma is divided schematically in T2 asthma (with an eosinophilic profile) and non T2 asthma (with a neutrophilic or mixed profiles). These patients have frequent exacerbations that can be triggered by infections, allergen exposure or pollutants. In this context, the pulmonary immunity team decipher the immunobiological mechanisms involved in asthma, to propose novel therapeutic targets, by using original experimental models of asthma, and cohorts of asthma patients. We have in particular shown in a T2 experimental model of house dust mite (HDM) allergic asthma that sensing by NOD1 of some bacteria associated to HDM aggravates the severity of asthma in vivo, and that inhibiting this pathway may be a therapeutic approach for asthma (Ait Yahia et al, J Allergy Clin Immunol, 2021). In another model of non T2 asthma induced by dog allergen and inducing a strong bronchial remodelling, inhibition of the pathway leading to IL-22 production attenuates this phenotype (Bouté et al, Allergy, 2021). You will find at the bottom of the page two 3D videos showing bronchial remodelling visualizing collagen fibers (in green) by two-photons microscopy in the lung at baseline, and after allergen challenge in the non T2 model (collaboration E Weirkmeister, Team microbiologie cellulaire et physique de l'infection). As there is currently no biotherapy targeting non T2 asthma, these results are very promising, and studies of proof of concept are underway (START AIRR funded by region Hauts de France) modified mice as well as in asthma patients.

Peribronchial type I collagen fibers are visualized in green through the generation of second harmonic (SHG) signals by two-photon microscopy in the lung at baseline. The other lung structures appear in red.

Peribronchial type I collagen fibers are visualized in green through the generation of second harmonic (SHG) signals by two-photon microscopy in the lung after dog allergen challenge. Note the triple helical collagen molecules around bronchi.


Our team studies the interactions between cells and tissues on the one hand, and bacteria, toxins, antimicrobial peptides and viruses on the other hand, by focusing on the mechanical and biological response. During the interaction, structural modifications are mechanically induced, which in turn will modulate a cellular or even tissue response.
The response we are studying is linked to the autophagy mechanism, which allows the cell to degrade microbes that enter the cells, but some of these microbes have developed, during the course of evolution, systems to escape or even exploit it.
Depending on the mechanical properties of the cells, structurally, the fluidity, elasticity and viscosity are modified. This concerns molecules, membranes and intracellular compartments. All of this helps to define the response capacity to the interaction between the micro-organism and the cell or tissue.
This is why we are developing a multidisciplinary approach combining biology and physics and designing innovative methods that enable us to remove conceptual barriers with regard to these interactions between host and microbes. If we can control these interactions or the responses they cause, then we can modulate their consequences.
We propose 4 short videos which, after a quick introduction on the general problem, describe subjects currently studied in the Group:
1- Mechanobiology from the molecule to the cell and tissue
2- Innovative technologies in host-pathogen interactions
3- Health benefits of lactic acid bacteria in the gut
4- Cellular responses to norovirus infections.

Have a good viewing!

 

Subjet #4

Subjet #3

Subjet #2

Subjet #1


Antibiotic (multi)drug resistance is a large and growing global health problem, particularly for tuberculosis and numerous nosocomial bacterial infections. In support of this, the World Health Organisation has proclaimed that research and drug development to combat these drug resistant bacteria is of critical priority. The CBA team investigates a series of novel strategies aimed to combat antibiotic resistant bacteria with current research focussing on the discovery and development of novel antibiotics and the development of innovate strategies that improve antibiotic penetration into bacteria.

To learn more about CBA team : HERE


The objectives of the team «Influenza, Immunity and metabolism» (I2M) are to better understand the physiopathological consequences of viral respiratory tract infections. We focus on influenza A virus and, more recently, on SARS-CoV-2, the aetiologic agent of COVID-19. We aim to study early immunological events developing in the lung tissue, and also outside the lungs. We integrate the impact of ageing and co-morbidities (dyslipidemia) in the host response to infection. This research recently led us to identify the gut-lung axis, and particularly the gut microbiota, as an important player of the host response. The adipose tissue is also sollicitated during infection and we try to disentangle the consequences on disease outcomes.  For this, we develop experimental models in link with clinicians. We expect that a better understanding of the gut/lung/adipose tissue axis will be instrumental in conceiving novel treatment options for patients.

To learn more about the team: HERE


OPINFIELD Team

One of our major focus concern the 3rd cause of death in the world: COPD.
You wish to discover more about it, and therapeutic application? Follow our series of 3 episodes.

Episode 3

Episode 2

Episode 1