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  1. Article ; Online: Enzyme mechanistic studies of NMA1982, a protein tyrosine phosphatase and potential virulence factor in Neisseria meningitidis

    Shuangding Wu / Mathieu Coureuil / Xavier Nassif / Lutz Tautz

    Scientific Reports, Vol 13, Iss 1, Pp 1-

    2023  Volume 10

    Abstract: Abstract Protein phosphorylation is an integral part of many cellular processes, not only in eukaryotes but also in bacteria. The discovery of both prokaryotic protein kinases and phosphatases has created interest in generating antibacterial therapeutics ...

    Abstract Abstract Protein phosphorylation is an integral part of many cellular processes, not only in eukaryotes but also in bacteria. The discovery of both prokaryotic protein kinases and phosphatases has created interest in generating antibacterial therapeutics that target these enzymes. NMA1982 is a putative phosphatase from Neisseria meningitidis, the causative agent of meningitis and meningococcal septicemia. The overall fold of NMA1982 closely resembles that of protein tyrosine phosphatases (PTPs). However, the hallmark C(X)5R PTP signature motif, containing the catalytic cysteine and invariant arginine, is shorter by one amino acid in NMA1982. This has cast doubt about the catalytic mechanism of NMA1982 and its assignment to the PTP superfamily. Here, we demonstrate that NMA1982 indeed employs a catalytic mechanism that is specific to PTPs. Mutagenesis experiments, transition state inhibition, pH-dependence activity, and oxidative inactivation experiments all support that NMA1982 is a genuine PTP. Importantly, we show that NMA1982 is secreted by N. meningitidis, suggesting that this protein is a potential virulence factor. Future studies will need to address whether NMA1982 is indeed essential for N. meningitidis survival and virulence. Based on its unique active site conformation, NMA1982 may become a suitable target for developing selective antibacterial drugs.
    Keywords Medicine ; R ; Science ; Q
    Subject code 612
    Language English
    Publishing date 2023-12-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: The netrin-1 receptor UNC5C contributes to the homeostasis of undifferentiated spermatogonia in adult mice

    Vilma Barroca / Chrystele Racine / Laurent Pays / Pierre Fouchet / Mathieu Coureuil / Isabelle Allemand

    Stem Cell Research, Vol 60, Iss , Pp 102723- (2022)

    2022  

    Abstract: In adult testis, the cell mobility is essential for spermatogonia differentiation and is suspected to regulate spermatogonial stem cell fate. Netrin-1 controls cell migration and/or survival according to the cellular context. Its involvement in some self- ...

    Abstract In adult testis, the cell mobility is essential for spermatogonia differentiation and is suspected to regulate spermatogonial stem cell fate. Netrin-1 controls cell migration and/or survival according to the cellular context. Its involvement in some self-renewing lineages raises the possibility that Netrin-1 could have a role in spermatogenesis.We show that in addition to Sertoli cells, a fraction of murine undifferentiated spermatogonia express the Netrin-1 receptor UNC5c and that UNC5c contributes to spermatogonia differentiation. Receptor loss in Unc5crcm males leads to the concomitant accumulation of transit-amplifying progenitors and short syncytia of spermatogonia. Without altering cell death rates, the consequences of Unc5c loss worsen with age: the increase in quiescent undifferentiated progenitors associated with a higher spermatogonial stem cell enriched subset leads to the spermatocyte I decline. We demonstrate in vitro that Netrin-1 promotes a guidance effect as it repulses both undifferentiated and differentiating spermatogonia.Finally, we propose that UNC5c triggers undifferentiated spermatogonia adhesion/ migration and that the repulsive activity of Netrin-1 receptors could regulate spermatogonia differentiation, and maintain germ cell homeostasis.
    Keywords Testis ; UNC5c ; Netrin-1 ; Undifferentiated Spermatogonia ; Mouse ; Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2022-04-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Implantation of engineered human microvasculature to study human infectious diseases in mouse models

    Sophia Schönherr-Hellec / Eirini Chatzopoulou / Jean-Philippe Barnier / Yoann Atlas / Sébastien Dupichaud / Thomas Guilbert / Yves Dupraz / Julie Meyer / Catherine Chaussain / Caroline Gorin / Xavier Nassif / Stephane Germain / Laurent Muller / Mathieu Coureuil

    iScience, Vol 26, Iss 4, Pp 106286- (2023)

    2023  

    Abstract: Summary: Animal models for studying human pathogens are crucially lacking. We describe the implantation in mice of engineered human mature microvasculature consisting of endothelial and perivascular cells embedded in collagen hydrogel that allows ... ...

    Abstract Summary: Animal models for studying human pathogens are crucially lacking. We describe the implantation in mice of engineered human mature microvasculature consisting of endothelial and perivascular cells embedded in collagen hydrogel that allows investigation of pathogen interactions with the endothelium, including in vivo functional studies. Using Neisseria meningitidis as a paradigm of human-restricted infection, we demonstrated the strength and opportunities associated with the use of this approach.
    Keywords Biological sciences ; Microbiology ; Bioengineering ; Cell biology ; Science ; Q
    Language English
    Publishing date 2023-04-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Type IV pilus retraction enables sustained bacteremia and plays a key role in the outcome of meningococcal sepsis in a humanized mouse model.

    Jean-Philippe Barnier / Daniel Euphrasie / Olivier Join-Lambert / Mathilde Audry / Sophia Schonherr-Hellec / Taliah Schmitt / Sandrine Bourdoulous / Mathieu Coureuil / Xavier Nassif / Mohamed El Behi

    PLoS Pathogens, Vol 17, Iss 2, p e

    2021  Volume 1009299

    Abstract: 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 ... ...

    Abstract 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 sustained bacteremia and lethality in a humanized mouse model. Intriguingly, although pilus-retraction deficient N. meningitidis strain (ΔpilT) efficiently colonizes human graft tissue, this mutant did not promote sustained bacteremia nor induce mouse lethality. This effect was not due to a decreased inflammatory response, nor defects in bacterial clearance by the innate immune system. Rather, TFP-retraction was necessary to promote the release of TFP-dependent contacts between bacteria and, in turn, the detachment from colonized microvessels. The resulting sustained bacteremia was directly correlated with lethality. Altogether, these results demonstrate that pilus retraction plays a key role in the occurrence and outcome of meningococcal sepsis by supporting sustained bacteremia. These findings open new perspectives on the role of circulating bacteria in the pathological alterations leading to lethal sepsis.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Airway environment drives the selection of quorum sensing mutants and promote Staphylococcus aureus chronic lifestyle

    Xiongqi Ding / Catherine Robbe-Masselot / Xiali Fu / Renaud Léonard / Benjamin Marsac / Charlene J. G. Dauriat / Agathe Lepissier / Héloïse Rytter / Elodie Ramond / Marion Dupuis / Daniel Euphrasie / Iharilalao Dubail / Cécile Schimmich / Xiaoquan Qin / Jessica Parraga / Maria Leite-de-Moraes / Agnes Ferroni / Benoit Chassaing / Isabelle Sermet-Gaudelus /
    Alain Charbit / Mathieu Coureuil / Anne Jamet

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 13

    Abstract: Abstract Staphylococcus aureus is a predominant cause of chronic lung infections. While the airway environment is rich in highly sialylated mucins, the interaction of S. aureus with sialic acid is poorly characterized. Using S. aureus USA300 as well as ... ...

    Abstract Abstract Staphylococcus aureus is a predominant cause of chronic lung infections. While the airway environment is rich in highly sialylated mucins, the interaction of S. aureus with sialic acid is poorly characterized. Using S. aureus USA300 as well as clinical isolates, we demonstrate that quorum-sensing dysfunction, a hallmark of S. aureus adaptation, correlates with a greater ability to consume free sialic acid, providing a growth advantage in an air-liquid interface model and in vivo. Furthermore, RNA-seq experiment reveals that free sialic acid triggers transcriptional reprogramming promoting S. aureus chronic lifestyle. To support the clinical relevance of our results, we show the co-occurrence of S. aureus, sialidase-producing microbiota and free sialic acid in the airway of patients with cystic fibrosis. Our findings suggest a dual role for sialic acid in S. aureus airway infection, triggering virulence reprogramming and driving S. aureus adaptive strategies through the selection of quorum-sensing dysfunctional strains.
    Keywords Science ; Q
    Subject code 610
    Language English
    Publishing date 2023-12-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Structure of the Neisseria meningitidis Type IV pilus

    Subramania Kolappan / Mathieu Coureuil / Xiong Yu / Xavier Nassif / Edward H. Egelman / Lisa Craig

    Nature Communications, Vol 7, Iss 1, Pp 1-

    2016  Volume 12

    Abstract: Type IV pili are present on a wide range of bacterial pathogens and mediate diverse functions. Here the authors report a high resolution crystal structure of the pilin subunit PilE, and a cryoEM reconstruction of the Type IV pilus filament from N. ... ...

    Abstract Type IV pili are present on a wide range of bacterial pathogens and mediate diverse functions. Here the authors report a high resolution crystal structure of the pilin subunit PilE, and a cryoEM reconstruction of the Type IV pilus filament from N. meningitidisthat offer insight into pilus assembly and functions.
    Keywords Science ; Q
    Language English
    Publishing date 2016-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: The pentose phosphate pathway constitutes a major metabolic hub in pathogenic Francisella.

    Héloise Rytter / Anne Jamet / Jason Ziveri / Elodie Ramond / Mathieu Coureuil / Pauline Lagouge-Roussey / Daniel Euphrasie / Fabiola Tros / Nicolas Goudin / Cerina Chhuon / Ivan Nemazanyy / Fabricio Edgar de Moraes / Carlos Labate / Ida Chiara Guerrera / Alain Charbit

    PLoS Pathogens, Vol 17, Iss 8, p e

    2021  Volume 1009326

    Abstract: Metabolic pathways are now considered as intrinsic virulence attributes of pathogenic bacteria and thus represent potential targets for antibacterial strategies. Here we focused on the role of the pentose phosphate pathway (PPP) and its connections with ... ...

    Abstract Metabolic pathways are now considered as intrinsic virulence attributes of pathogenic bacteria and thus represent potential targets for antibacterial strategies. Here we focused on the role of the pentose phosphate pathway (PPP) and its connections with other metabolic pathways in the pathophysiology of Francisella novicida. The involvement of the PPP in the intracellular life cycle of Francisella was first demonstrated by studying PPP inactivating mutants. Indeed, we observed that inactivation of the tktA, rpiA or rpe genes severely impaired intramacrophage multiplication during the first 24 hours. However, time-lapse video microscopy demonstrated that rpiA and rpe mutants were able to resume late intracellular multiplication. To better understand the links between PPP and other metabolic networks in the bacterium, we also performed an extensive proteo-metabolomic analysis of these mutants. We show that the PPP constitutes a major bacterial metabolic hub with multiple connections to glycolysis, the tricarboxylic acid cycle and other pathways, such as fatty acid degradation and sulfur metabolism. Altogether our study highlights how PPP plays a key role in the pathogenesis and growth of Francisella in its intracellular niche.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 570 ; 571
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Sialic acid mediated mechanical activation of β2 adrenergic receptors by bacterial pili

    Zoe Virion / Stéphane Doly / Kusumika Saha / Mireille Lambert / François Guillonneau / Camille Bied / Rebecca M. Duke / Pauline M. Rudd / Catherine Robbe-Masselot / Xavier Nassif / Mathieu Coureuil / Stefano Marullo

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 14

    Abstract: Meningococcus utilizes β-arrestin selective activation of endothelial cell β2 adrenergic receptor (β2AR) to cause meningitis in humans. Here authors report that Meningococcus triggers β2AR signaling by exerting forces on β2AR glycans that terminally ... ...

    Abstract Meningococcus utilizes β-arrestin selective activation of endothelial cell β2 adrenergic receptor (β2AR) to cause meningitis in humans. Here authors report that Meningococcus triggers β2AR signaling by exerting forces on β2AR glycans that terminally expose N-acetyl-neuraminic acid (sialic acid, Neu5Ac) residues.
    Keywords Science ; Q
    Language English
    Publishing date 2019-10-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Sialic acid mediated mechanical activation of β2 adrenergic receptors by bacterial pili

    Zoe Virion / Stéphane Doly / Kusumika Saha / Mireille Lambert / François Guillonneau / Camille Bied / Rebecca M. Duke / Pauline M. Rudd / Catherine Robbe-Masselot / Xavier Nassif / Mathieu Coureuil / Stefano Marullo

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 14

    Abstract: Meningococcus utilizes β-arrestin selective activation of endothelial cell β2 adrenergic receptor (β2AR) to cause meningitis in humans. Here authors report that Meningococcus triggers β2AR signaling by exerting forces on β2AR glycans that terminally ... ...

    Abstract Meningococcus utilizes β-arrestin selective activation of endothelial cell β2 adrenergic receptor (β2AR) to cause meningitis in humans. Here authors report that Meningococcus triggers β2AR signaling by exerting forces on β2AR glycans that terminally expose N-acetyl-neuraminic acid (sialic acid, Neu5Ac) residues.
    Keywords Science ; Q
    Language English
    Publishing date 2019-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: An ADAM-10 dependent EPCR shedding links meningococcal interaction with endothelial cells to purpura fulminans.

    Hervé Lécuyer / Zoé Virion / Jean-Philippe Barnier / Soraya Matczak / Sandrine Bourdoulous / Elsa Bianchini / François Saller / Delphine Borgel / Xavier Nassif / Mathieu Coureuil

    PLoS Pathogens, Vol 14, Iss 4, p e

    2018  Volume 1006981

    Abstract: Purpura fulminans is a deadly complication of Neisseria meningitidis infections due to extensive thrombosis of microvessels. Although a Disseminated Intra-vascular Coagulation syndrome (DIC) is frequently observed during Gram negative sepsis, it is ... ...

    Abstract Purpura fulminans is a deadly complication of Neisseria meningitidis infections due to extensive thrombosis of microvessels. Although a Disseminated Intra-vascular Coagulation syndrome (DIC) is frequently observed during Gram negative sepsis, it is rarely associated with extensive thrombosis like those observed during meningococcemia, suggesting that the meningococcus induces a specific dysregulation of coagulation. Another specific feature of N. meningitidis pathogenesis is its ability to colonize microvessels endothelial cells via type IV pili. Importantly, endothelial cells are key in controlling the coagulation cascade through the activation of the potent anticoagulant Protein C (PC) thanks to two endothelial cell receptors among which the Endothelial Protein C Receptor (EPCR). Considering that congenital or acquired deficiencies of PC are associated with purpura fulminans, we hypothesized that a defect in the activation of PC following meningococcal adhesion to microvessels is responsible for the thrombotic events observed during meningococcemia. Here we showed that the adhesion of N. meningitidis on endothelial cells results in a rapid and intense decrease of EPCR expression by inducing its cleavage in a process know as shedding. Using siRNA experiments and CRISPR/Cas9 genome edition we identified ADAM10 (A Disintegrin And Metalloproteinase-10) as the protease responsible for this shedding. Surprisingly, ADAM17, the only EPCR sheddase described so far, was not involved in this process. Finally, we showed that this ADAM10-mediated shedding of EPCR induced by the meningococcal interaction with endothelial cells was responsible for an impaired activation of Protein C. This work unveils for the first time a direct link between meningococcal adhesion to endothelial cells and a severe dysregulation of coagulation, and potentially identifies new therapeutic targets for meningococcal purpura fulminans.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2018-04-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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