Les interleukines sont des médiateurs protéiques solubles qui peuvent déclencher une activation cellulaire. D’abord impliquée dans l’activation des cellules T dans la production d’immunoglobulines par les cellules B, l’interleukine 6... more
Les interleukines sont des médiateurs protéiques solubles qui peuvent déclencher une activation cellulaire. D’abord impliquée dans l’activation des cellules T dans la production d’immunoglobulines par les cellules B, l’interleukine 6 (IL6) provoque aussi l’induction de protéines de la phase aiguë par les hépatocytes. Ainsi, l’IL6 est impliquée dans les processus inflammatoires qui sont en grande partie responsables de la pathogénie de la cowdriose. Originellement produit par des macrophages et des cellules endothéliales activées, l’IL6 agit comme un stimulant de la réponse immunitaire. Néanmoins, quand elle est produite constamment et en grandes quantités, l’IL6 provoque des réactions inflammatoires non contrôlées. Afin de tester si l’IL6 est impliquée dans la cowdriose, une culture primaire de cellules endothéliales de cerveau bovin (BBEC) a été infectée in vitro par C. ruminantium. Les cellules infectées ont été récoltées tous les jours et ce jusqu’au sixième jour où toutes les ce...
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Neisseria meningitidis (meningococcus) is a Gram-negative bacterium responsible for two devastating forms of invasive diseases: purpura fulminans and meningitis. Since the first description of the epidemic nature of the illness at the... more
Neisseria meningitidis (meningococcus) is a Gram-negative bacterium responsible for two devastating forms of invasive diseases: purpura fulminans and meningitis. Since the first description of the epidemic nature of the illness at the dawn of the nineteenth century, the scientific knowledge of meningococcal infection has increased greatly. Major advances have been made in the management of the disease with the advent of antimicrobial therapy and the implementation of meningococcal vaccines. More recently, an extensive knowledge has been accumulated on meningococcal interaction with its human host, revealing key processes involved in disease progression and new promising therapeutic approaches.
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Therapies targeting the tyrosine kinase receptor HER2 have significantly improved survival of patients with HER2+ cancer. However, both de novo and acquired resistance remain a challenge, particularly in the brain metastatic setting. Here... more
Therapies targeting the tyrosine kinase receptor HER2 have significantly improved survival of patients with HER2+ cancer. However, both de novo and acquired resistance remain a challenge, particularly in the brain metastatic setting. Here we report that, unlike other HER tyrosine kinase receptors, HER2 possesses a binding motif in its cytosolic juxtamembrane region that allows interaction with members of the Ezrin/Radixin/Moesin (ERM) family. Under physiologic conditions, this interaction controls the localization of HER2 in ERM-enriched domains and stabilizes HER2 in a catalytically repressed state. In HER2+ breast cancers, low expression of Moesin correlated with increased HER2 expression. Restoring expression of ERM proteins in HER2+ breast cancer cells was sufficient to revert HER2 activation and inhibit HER2-dependent proliferation. A high-throughput assay recapitulating the HER2–ERM interaction allowed for screening of about 1,500 approved drugs. From this screen, we found Zuc...
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Bacterial pathogens are internalized into non-phagocytic cells either by a zipper mechanism involving a direct contact between a bacterial ligand and a cellular receptor or a trigger mechanism secondary to the formation of membrane... more
Bacterial pathogens are internalized into non-phagocytic cells either by a zipper mechanism involving a direct contact between a bacterial ligand and a cellular receptor or a trigger mechanism secondary to the formation of membrane ruffles. Here we show that internalization of capsulated Neisseria meningitidis within endothelial cells following type IV pilus-mediated adhesion is associated with the formation of cellular protrusions at the site of bacterial attachment. These protrusions, like microvilli, are highly enriched in ezrin and moesin, two members of the ERM(ezrin/radixin/moesin) family, whereas vinculin and paxillin are absent. ERM-binding transmembrane proteins, such as CD44, and cortical actin polymerization colocalized within these membrane protrusions. Expression of dominant-negative ezrin largely prevented cortical actin polymerization, thus confirming the role of this molecule in bacteria-induced cytoskeletal modifications. Moreover, using selective inhibitors and dom...
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Bacterial infections are frequently based on the binding of lectin-like adhesins to specific glycan determinants exposed on host cell receptors. These interactions confer species-specific recognition and tropism for particular host... more
Bacterial infections are frequently based on the binding of lectin-like adhesins to specific glycan determinants exposed on host cell receptors. These interactions confer species-specific recognition and tropism for particular host tissues and represent attractive antibacterial targets. However, the wide structural diversity of carbohydrates hampers the characterization of specific glycan determinants. Here, we characterized the receptor recognition of type IV pili (Tfp), a key adhesive factor present in numerous bacterial pathogens, using Neisseria meningitidis as a model organism. We found that meningococcal Tfp specifically recognize a triantennary sialylated poly- N -acetyllactosamine–containing N -glycan exposed on the human receptor CD147/Basigin, while fucosylated derivatives of this N -glycan impaired bacterial adhesion. Corroborating the inhibitory role of fucosylation on receptor recognition, adhesion of the meningococcus on nonhuman cells expressing human CD147 required p...
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Research Interests: Pharmacology, Biochemistry, Neuroscience, Physiology, Chemistry, and 15 moreHematology, Developmental Biology, Molecular Biology, Biotechnology, Cancer, Cell Migration, Cell Biology, Infectious Diseases, Medicine, Rr, BBB, Molecular Pharmaceutics, Human Brain Endothelial Cells, Cannabidiol, and Pharmacology and pharmaceutical sciences
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Neisseria meningitidis is a leading cause of bacterial meningitis and septicemia, affecting infants and adults worldwide. N. meningitidis is also a common inhabitant of the human nasopharynx and, as such, is highly adapted to its niche.... more
Neisseria meningitidis is a leading cause of bacterial meningitis and septicemia, affecting infants and adults worldwide. N. meningitidis is also a common inhabitant of the human nasopharynx and, as such, is highly adapted to its niche. During bacteremia, N. meningitidis gains access to the blood compartment, where it adheres to endothelial cells of blood vessels and causes dramatic vascular damage. Colonization of the nasopharyngeal niche and communication with the different human cell types is a major issue of the N. meningitidis life cycle that is poorly understood. Here, highly saturated random transposon insertion libraries of N. meningitidis were engineered, and the fitness of mutations during routine growth and that of colonization of endothelial and epithelial cells in a flow device were assessed in a transposon insertion site sequencing (Tn-seq) analysis. This allowed the identification of genes essential for bacterial growth and genes specifically required for host cell co...
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ErbB2 is a receptor tyrosine kinase belonging to the family of epidermal growth factor (EGF) receptors which is generally involved in cell differentiation, proliferation, and tumor growth, and activated by heterodimerization with the... more
ErbB2 is a receptor tyrosine kinase belonging to the family of epidermal growth factor (EGF) receptors which is generally involved in cell differentiation, proliferation, and tumor growth, and activated by heterodimerization with the other members of the family. We show here that type IV pilus–mediated adhesion of Neisseria meningitidis onto endothelial cells induces tyrosyl phosphorylation and massive recruitment of ErbB2 underneath the bacterial colonies. However, neither the phosphorylation status nor the cellular localization of the EGF receptors, ErbB3 or ErbB4, were affected in infected cells. ErbB2 phosphorylation induced by N. meningitidis provides docking sites for the kinase src and leads to its subsequent activation. Specific inhibition of either ErbB2 and/or src activity reduces bacterial internalization into endothelial cells without affecting bacteria-induced actin cytoskeleton reorganization or ErbB2 recruitment. Moreover, inhibition of both actin polymerization and t...
Research Interests: Fluorescence Microscopy, Biology, Enzyme Inhibitors, Cell Biology, Medicine, and 15 moreSignal Transduction, Biological Sciences, Cell line, Humans, Phosphorylation, CORTACTIN, Endothelial cell, ENDOTHELIUM, Bacterial Adhesion, Protein Tyrosine Phosphatases, Receptor Tyrosine Kinase, Quinazolines, Neisseria meningitidis, Src family kinases, and Medical and Health Sciences
Adherent cells assemble fibronectin into a fibrillar matrix on their apical surface. The fibril formation is initiated by fibronectin binding to the integrins α5β1 and αvβ3, and is completed by a process that includes fibronectin... more
Adherent cells assemble fibronectin into a fibrillar matrix on their apical surface. The fibril formation is initiated by fibronectin binding to the integrins α5β1 and αvβ3, and is completed by a process that includes fibronectin self-assembly. We found that a 76– amino acid fragment of fibronectin (III1-C) that forms one of the self-assembly sites caused disassembly of preformed fibronectin matrix without affecting cell adhesion. Treating attached fibroblasts or endothelial cells with III1-C inhibited cell migration and proliferation. Rho-dependent stress fiber formation and Rho-dependent focal contact protein phosphorylation were also inhibited, whereas Cdc42 was activated, leading to actin polymerization into filopodia. ACK (activated Cdc42-binding kinase) and p38 MAPK (mitogen-activated protein kinase), two downstream effectors of Cdc42, were activated, whereas PAK (p21-activated kinase) and JNK/SAPK (c-Jun NH2-terminal kinase/ stress-activated protein kinase) were inhibited. II...
Research Interests: Biology, Cell Migration, Cell Cycle, Cell Biology, Medicine, and 15 moreExtracellular Matrix, Cytoskeleton, Biological Sciences, Humans, Mitogen Activated Protein Kinase, Endothelial cell, Amino Acid Profile, Protein Kinase, Growth Factor, Human Fibroblasts, Cell Cycle Proteins, Gtp Binding Proteins, Laminin, fibroblasts, and Medical and Health Sciences
Breaking the Barrier Being able to deliver drugs into the brain to treat degenerative diseases such as Alzheimer's or Parkinson's requires the ability to traverse the blood-brain barrier (BBB). Understanding the formation of the... more
Breaking the Barrier Being able to deliver drugs into the brain to treat degenerative diseases such as Alzheimer's or Parkinson's requires the ability to traverse the blood-brain barrier (BBB). Understanding the formation of the very specific adherent junctions (AJ) and tight junctions present at the BBB cell junctions is a prerequisite to the design of such therapeutics. However, diminishing the expression of any one component involved in the formation of these intercellular junctions destroys them. Coureuil et al. (p. 83 , published online 11 June) exploited the specific recruitment of AJ proteins by Neisseria meningitidis to dissect this process. Adhesion of the bacteria to human brain endothelial cells recruited the polarity complex Par3/Par6/PKCζ required for the establishment of eukaryotic cell polarity and the formation of intercellular junctions. The bacterial recruitment of the polarity complex depleted junctional proteins at the cell-cell interface opening the inte...
Research Interests: Science, Biology, Membrane Proteins, Medicine, Multidisciplinary, and 15 moreCell line, Brain, Humans, Endothelial Cells, Blood brain barrier, Cell Polarity, Human Brain, Endothelial cell, Meningitis, Cell Cycle Proteins, Bacterial Adhesion, Cell Adhesion Molecules, Cadherins, Protein Kinase C, and Neisseria meningitidis
The lecticans are a family of chondroitin sulfate proteoglycans including aggrecan, versican, neurocan, and brevican. The C-terminal globular domains of lecticans are structurally related to selectins, consisting of a C-type lectin domain... more
The lecticans are a family of chondroitin sulfate proteoglycans including aggrecan, versican, neurocan, and brevican. The C-terminal globular domains of lecticans are structurally related to selectins, consisting of a C-type lectin domain flanked by epidermal growth factor and complement regulatory protein domains. The C-type lectin domain of versican has been shown to bind tenascin-R, an extracellular matrix protein specifically expressed in the nervous system, and the interaction was presumed to be mediated by a carbohydrate–protein interaction. In this paper, we show that the C-type lectin domain of brevican, another lectican that is specifically expressed in the nervous system, also binds tenascin-R. Surprisingly, this interaction is mediated by a protein–protein interaction through the fibronectin type III domains 3–5 of tenascin-R, independent of any carbohydrates or sulfated amino acids. The lectin domains of versican and other lecticans also bind the same domain of tenascin-...
Research Interests: Multidisciplinary, Extracellular Matrix, Cell line, Animals, Lectins, and 15 moreSurface plasmon resonance, Rat Brain, Protein Interaction, Epidermal Growth Factor, Protein Domains, Rats, Carbohydrate metabolism, Amino Acid Profile, CARBOHYDRATES, Nervous System, Chondroitin Sulfate, Protein Binding, Ligands, Extracellular Matrix Proteins, and Tenascin
Research Interests: Pharmacogenomics, Sickle Cell Anemia, Flow Cytometry, Biology, Medicine, and 15 moreGene expression, Cell line, Humans, Endothelial Cells, Sickle Cell Disease, Disease Severity, Vascular endothelium, mRna expression levels, Endothelial cell, Red blood cell, Hydroxyurea, Vascular Endothelial Function, Hydroxycarbamide, reverse transcriptase polymerase chain reaction, and Pharmacology and pharmaceutical sciences
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Research Interests: Neurochemistry, Interaction, Enzyme Inhibitors, Cell Biology, Adhesion, and 15 moreCytoskeleton, Endothelial Cells, Mice, Blood brain barrier, Animals, Monoclonal Antibodies, Phosphorylation, Immunoprecipitation, CORTACTIN, Rats, Signaling pathways, Endothelial cell, Adhesion molecules, Protein Tyrosine Phosphatases, and Neurosciences
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Type-IV-pilus-mediated adhesion of Neisseria meningitidis (also known as meningococcus) to human endothelial cells induces the formation of membrane protrusions leading to bacterial uptake. We have previously shown that these protrusions... more
Type-IV-pilus-mediated adhesion of Neisseria meningitidis (also known as meningococcus) to human endothelial cells induces the formation of membrane protrusions leading to bacterial uptake. We have previously shown that these protrusions result from a Rho- and Cdc42-dependent cortical actin polymerization, and from the activation of the ErbB2 tyrosine-kinase receptor and the Src kinase, leading to tyrosine phosphorylation of cortactin. We report here that N. meningitidis mutants expressing a deglycosylated lipo-oligosaccharide are poorly invasive. These mutants show structurally altered actin polymerization. Moreover, although they efficiently recruit and activate ErbB2 and Src, these mutants are defective in the recruitment and phosphorylation of cortactin. We demonstrate that phosphorylated cortactin controls the cortical actin polymerization, which leads to membrane protrusion formation. In addition, we show that cortactin recruitment is dependent on the activation of a phosphoin...
Research Interests: Biology, Cell Adhesion, Cell Biology, Medicine, Signal Transduction, and 15 moreBiological Sciences, Humans, Endothelial Cells, Mutation, Tyrosine Kinase Receptor, Actin Cytoskeleton, Lipopolysaccharides, Phagocytosis, Endothelial cell, Cell communication, Tyrosine Phosphorylation, Neisseria meningitidis, Src family kinases, Medical and Health Sciences, and signalling pathway
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Retinoic acid induces clinical remission in acute promyelocytic leukemia (APL) by triggering differentiation of leukemia promyelocytes. Here, we have characterized a gene encoding a member of the immunoglobulin superfamily, among novel... more
Retinoic acid induces clinical remission in acute promyelocytic leukemia (APL) by triggering differentiation of leukemia promyelocytes. Here, we have characterized a gene encoding a member of the immunoglobulin superfamily, among novel retinoic acid–induced genes identified in APL cells. This protein, which was named JAML (junctional adhesion molecule–like), contains 2 extracellular immunoglobulin-like domains, a transmembrane segment, and a cytoplasmic tail. JAML mRNA is expressed in hematopoietic tissues and is prominently expressed in granulocytes. The fact that JAML protein is localized at the cell plasma membrane in the areas of cell-cell contacts, whereas it is not detected at free cell borders, suggests that JAML is engaged in homophilic interactions. Furthermore, a conserved dimerization motif among JAM members was shown to be important for JAML localization at the cell membrane. Finally, exogenous expression of JAML in myeloid leukemia cells resulted in enhanced cell adhesi...
Research Interests: Biology, Cell Adhesion, Medicine, Acute Myeloid Leukemia, Cell Differentiation, and 15 moreHumans, Blood, Clinical Sciences, Endothelial cell, Base Sequence, Junctional adhesion molecule, Plasma Membrane, Leukocytes, Acute Promyelocytic Leukemia, Gene Expression Regulation, Cell Adhesion Molecules, Molecular Sequence Data, Cell Membrane, Cardiovascular medicine and haematology, and Paediatrics and reproductive medicine
International audienceNeisseria meningitidis (meningococcus) is a Gram-negative bacterium responsible for two devastating forms of invasive diseases: purpura fulminans and meningitis. Since the first description of the epidemic nature of... more
International audienceNeisseria meningitidis (meningococcus) is a Gram-negative bacterium responsible for two devastating forms of invasive diseases: purpura fulminans and meningitis. Since the first description of the epidemic nature of the illness at the dawn of the nineteenth century, the scientific knowledge of meningococcal infection has increased greatly. Major advances have been made in the management of the disease with the advent of antimicrobial therapy and the implementation of meningococcal vaccines. More recently, an extensive knowledge has been accumulated on meningococcal interaction with its human host, revealing key processes involved in disease progression and new promising therapeutic approaches.Neisseria meningitidis (méningocoque) est une bactérie à Gram négatif responsable de deux formes gravissimes de maladies invasives : le purpura fulminans et la méningite. Depuis la première description du caractère épidémique de la maladie à l'aube du 19e siècle, les c...
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Neisseria meningitidis (the meningococcus) remains a major cause of bacterial meningitis and fatal sepsis. This commensal bacterium of the human nasopharynx can cause invasive diseases when it leaves its niche and reaches the bloodstream.... more
Neisseria meningitidis (the meningococcus) remains a major cause of bacterial meningitis and fatal sepsis. This commensal bacterium of the human nasopharynx can cause invasive diseases when it leaves its niche and reaches the bloodstream. Blood-borne meningococci have the ability to adhere to human endothelial cells and rapidly colonize microvessels. This crucial step enables dissemination into tissues and promotes deregulated inflammation and coagulation, leading to extensive necrotic purpura in the most severe cases. Adhesion to blood vessels relies on type IV pili (TFP). These long filamentous structures are highly dynamic as they can rapidly elongate and retract by the antagonistic action of two ATPases, PilF and PilT. However, the consequences of TFP dynamics on the pathophysiology and the outcome of meningococcal sepsis in vivo have been poorly studied. Here, we show that human graft microvessels are replicative niches for meningococci, that seed the bloodstream and promote su...
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Neisseria meningitidis (meningococcus) is an invasive bacterial pathogen that colonizes human vessels, causing thrombotic lesions and meningitis. Establishment of tight interactions with endothelial cells is crucial for meningococci to... more
Neisseria meningitidis (meningococcus) is an invasive bacterial pathogen that colonizes human vessels, causing thrombotic lesions and meningitis. Establishment of tight interactions with endothelial cells is crucial for meningococci to resist haemodynamic forces. Two endothelial receptors, CD147 and the β2-adrenergic receptor (β2AR), are sequentially engaged by meningococci to adhere and promote signalling events leading to vascular colonization, but their spatiotemporal coordination is unknown. Here we report that CD147 and β2AR form constitutive hetero-oligomeric complexes. The scaffolding protein α-actinin-4 directly binds to the cytosolic tail of CD147 and governs the assembly of CD147-β2AR complexes in highly ordered clusters at bacterial adhesion sites. This multimolecular assembly process increases the binding strength of meningococci to endothelial cells under shear stress, and creates molecular platforms for the elongation of membrane protrusions surrounding adherent bacter...