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1. Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups

Author

María-Jesús Lobón-Iglesias, Mamy Andrianteranagna, Zhi-Yan Han, Céline Chauvin, Julien Masliah-Planchon, Valeria Manriquez, Arnault Tauziede-Espariat, Sandrina Turczynski, Rachida Bouarich-Bourimi, Magali Frah, Christelle Dufour, Thomas Blauwblomme, Liesbeth Cardoen, Gaelle Pierron, Laetitia Maillot, Delphine Guillemot, Stéphanie Reynaud, Christine Bourneix, Célio Pouponnot, Didier Surdez, Mylene Bohec, Sylvain Baulande, Olivier Delattre, Eliane Piaggio, Olivier Ayrault, Joshua J. Waterfall, Nicolas Servant, Kevin Beccaria, Volodia Dangouloff-Ros, and Franck Bourdeaut

Subjects
Science
Abstract

Abstract Atypical teratoid rhabdoid tumors (ATRT) are divided into MYC, TYR and SHH subgroups, suggesting diverse lineages of origin. Here, we investigate the imaging of human ATRT at diagnosis and the precise anatomic origin of brain tumors in the Rosa26-CreERT2::Smarcb1flox/flox model. This cross-species analysis points to an extra-cerebral origin for MYC tumors. Additionally, we clearly distinguish SHH ATRT emerging from the cerebellar anterior lobe (CAL) from those emerging from the basal ganglia (BG) and intra-ventricular (IV) regions. Molecular characteristics point to the midbrain-hindbrain boundary as the origin of CAL SHH ATRT, and to the ganglionic eminence as the origin of BG/IV SHH ATRT. Single-cell RNA sequencing on SHH ATRT supports these hypotheses. Trajectory analyses suggest that SMARCB1 loss induces a de-differentiation process mediated by repressors of the neuronal program such as REST, ID and the NOTCH pathway.

Published
2023
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2. SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance

Author

Bujamin H. Vokshi, Guillaume Davidson, Nassim Tawanaie Pour Sedehi, Alexandra Helleux, Marc Rippinger, Alexandre R. Haller, Justine Gantzer, Jonathan Thouvenin, Philippe Baltzinger, Rachida Bouarich, Valeria Manriquez, Sakina Zaidi, Priya Rao, Pavlos Msaouel, Xiaoping Su, Hervé Lang, Thibault Tricard, Véronique Lindner, Didier Surdez, Jean-Emmanuel Kurtz, Franck Bourdeaut, Nizar M. Tannir, Irwin Davidson, and Gabriel G. Malouf

Subjects
Science
Abstract

Abstract Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into an epithelial-mesenchymal gradient of RMC cells associated with loss of renal epithelial transcription factors TFCP2L1, HOXB9 and MITF and gain of MYC and NFE2L2-associated oncogenic and ferroptosis resistance programs. We describe the molecular basis for this transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferroptosis resistance programs leading to ferroptotic cell death. Ferroptosis resistance links TAL cell survival with the high extracellular medullar iron concentrations associated with sickle cell trait, an environment propitious to the mutagenic events associated with RMC development. This unique environment may explain why RMC is the only SMARCB1-deficient tumour arising from epithelial cells, differentiating RMC from rhabdoid tumours arising from neural crest cells.

Published
2023
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3. Colonization of dermal arterioles by Neisseria meningitidis provides a safe haven from neutrophils

Author

Valeria Manriquez, Pierre Nivoit, Tomas Urbina, Hebert Echenique-Rivera, Keira Melican, Marie-Paule Fernandez-Gerlinger, Patricia Flamant, Taliah Schmitt, Patrick Bruneval, Dorian Obino, and Guillaume Duménil

Subjects
Science
Abstract

The human pathogen Neisseria meningitidis colonizes blood vessels and causes vascular damage, despite a neutrophil-rich inflammatory infiltrate. Here, Manriquez et al. use a humanized mouse model to show that pathogen colonization of capillaries and arterioles creates an intravascular niche that precludes an effective action of neutrophils.

Published
2021
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4. Adhesion to nanofibers drives cell membrane remodeling through one-dimensional wetting

Author

Arthur Charles-Orszag, Feng-Ching Tsai, Daria Bonazzi, Valeria Manriquez, Martin Sachse, Adeline Mallet, Audrey Salles, Keira Melican, Ralitza Staneva, Aurélie Bertin, Corinne Millien, Sylvie Goussard, Pierre Lafaye, Spencer Shorte, Matthieu Piel, Jacomine Krijnse-Locker, Françoise Brochard-Wyart, Patricia Bassereau, and Guillaume Duménil

Subjects
Science
Abstract

Meningococci remodel the plasma membrane of host cells during infection. Here, Charles-Orszag et al. show that plasma membrane remodeling occurs independently of F-actin, along meningococcal type IV pili fibers, by a physical mechanism that they term ‘one-dimensional’ membrane wetting.

Published
2018
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6. Colonization of dermal arterioles by Neisseria meningitidis provides a safe haven from neutrophils

Author

Pierre Nivoit, Patrick Bruneval, Patricia Flamant, Keira Melican, Tomas Urbina, Valeria Manriquez, Guillaume Duménil, Dorian Obino, Hebert Echenique-Rivera, and Taliah Schmitt

Subjects
Endothelium, Cell adhesion molecule, Neisseria meningitidis, Phagocytosis, Fulminant, Biology, medicine.disease_cause, medicine.disease, Microbiology, medicine.anatomical_structure, Humanized mouse, medicine, Meningitis, Pathogen
Abstract

Neisseria meningitidis, a human-specific bacterium, is responsible for meningitis and fatal fulminant systemic disease. Bacteria colonize blood vessels, rapidly causing devastating vascular damage despite a neutrophil-rich inflammatory infiltrate. How this pathogen escapes the neutrophil response is unknown. Using a humanized mouse model, we show that vascular colonization leads to the recruitment of neutrophils, partially reducing bacterial burden and vascular damage. This partial effect is due to the ability of bacteria to indiscriminately colonize capillaries, venules and arterioles, as observed in human samples. In venules, potent neutrophil recruitment allows efficient bacterial phagocytosis. In contrast, in infected capillaries and arterioles adhesion molecules such as E-Selectin are not expressed on the endothelium and intravascular neutrophil recruitment is minimal. These results show that colonization of capillaries and arterioles by N. meningitidis create an intravascular niche that preclude the action of neutrophils, resulting in immune escape and subsequent fulminant progression of the infection.

Published
2021
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7. ATRT-11. Anatomico-biological correlations define a new layer for ATRT molecular subgroups pointing to potential lineages of origin

Author

Maria Lobon-Iglesias, Mamy Andrianteranagna, Zhi-Yan Han, Julien Masliah-Planchon, Arnault Tauziede-Espariat, Magali Frah, Christelle Dufour, Celine Chauvin, Rachida Bouarich, Valeria Manriquez, Sandrina Turczinski, Olivier Delattre, Sylvain Baulande, Olivier Ayrault, Nicolas Servant, Kevin Beccaria, Volodia Dangouloff-Ros, and Franck Bourdeaut

Subjects
Cancer Research, Oncology, Neurology (clinical)
Abstract

Atypical teratoid rhabdoid tumors (ATRT) are divided in three molecular subgroups, the so-called MYC, TYR and SHH subgroups. This heterogeneity suggests some diversity in the cells of origin, which remain hypothetical thus far. A careful radiological review of 55 MRI at diagnosis was performed in parallel with a careful analysis of mouse tumor origin in the Rosa26-CreERT2::Smarcbflox/flox model. Methylation, bulk RNAseq and scRNAseq analyses were integrated to these anatomic information to highlight potential origin for each molecularly and anatomically defined subgroups. We demonstrated that mouse Myc-ATRTs derive from extra-parenchymal meningeal areas, a finding consistant with many human MYC ATRT being clearly of intra-cranial extra-axial origin. Although this finding could point to a neural crest origin, transcriptomic features fail to unravel any lineage-specific signature. We also defined a distinct supra-tentorial SHH ATRT subgroup, characterized both in mouse and Humans by neural features pointing to the ganglionic eminence progenitors as the candidate origin. Finally we identified a distinct infra-tentorial SHH ATRT subgroup, not observed in mice, with hindbrain/midbrain boundary progenitor signature. scRNAseq from human SHH infra-tentorial tumors consistently suggest a dedifferentiation process involving the Notch pathway in the oncogenic transformation of hindbrain/midbrain neural progenitors.

Published
2022
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9. Clonally Expanded T Cells Reveal Immunogenicity of Rhabdoid Tumors

Author

Sonia Lameiras, Pamela Caudana, Sylvain Baulande, Arnault Tauziède-Espariat, Nicolas Servant, Franck Bourdeaut, Amaury Leruste, Joshua J. Waterfall, Didier Surdez, Mamy Andrianteranagna, Stéphanie Puget, Sandrine Grossetête-Lalami, Eliane Piaggio, Christine Sedlik, Jimena Tosello, Mylène Bohec, Philippe Benaroch, Rodrigo Nalio Ramos, Celio Pouponnot, Jovan Nikolic, Julie Helft, Solene Brohard, Valeria Manriquez, Louise Galmiche, Leticia Laura Niborski, Olivier Delattre, Aurore Coulomb, Zhi-Yan Han, Céline Chauvin, Kevin Beccaria, Julien Masliah-Planchon, Wilfrid Richer, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Paris sciences et lettres (PSL), Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathology Department [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Gene and Cell Medicine [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Sorbonne Paris Cité, Immunité et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, This work was funded by the BMS and the Janssen Horizon Foundations, the Société Française des Cancers de l’Enfant (SFCE) with the associations 'Enfants et Santé' and 'L’Étoile de Martin,' INCA PL-BIO 2016 call for Project from the French Minister of Research, the 'Abigael,' 'ADAM,' 'Au Nom d’Andréa,' and 'Marabout de Ficelles' associations. RTOP team is supported by the SiRIC-Curie Program (grant INCa-DGOS-4654). INSERM U830 is supported by the Institut National de la Santé et de la Recherche Médicale, Curie Institute and the Ligue Nationale Contre Le Cancer. TransImm team is supported by the SiRIC-Curie Program (grant INCa-DGOS-12554), the LabEx DCBIOL (ANR-10-IDEX-0001-02 PSL and ANR-11-LABX-0043), and the Center of Clinical Investigation (CIC IGR-Curie 1428). A.L. and P.C. were supported by the PhD program of Curie Institute., The authors thank S. Cairo, M. Chicard, J. Denizeau, C. Goudot, P. Gueguen, I. Jimenez, N. Manel, A. Pinto, S. Viel, S. Zaidi, and the mouse and the cytometry facility cores at Curie Institute., Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL), PSL Research University (PSL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie, Signalisation normale et pathologique de l'embryon aux thérapies innovante des cancers, Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie pathologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), and Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Cancer Research, Chromosomal Proteins, Non-Histone, medicine.medical_treatment, T-Lymphocytes, [SDV]Life Sciences [q-bio], SMARCB1, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, single-cell RNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Immune system, endogenous retrovirus, medicine, Animals, Humans, tumor immunology, AT/RT, rhabdoid tumor, Immunogenicity, T-cell receptor, Nuclear Proteins, Cell Biology, Immunotherapy, Chromatin Assembly and Disassembly, Pediatric cancer, Immunohistochemistry, SWI/SNF, 3. Good health, Chromatin, pediatric cancer, DNA-Binding Proteins, Mice, Inbred C57BL, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Mutation, Cancer research, immunotherapy, T cell receptor, CD8, Transcription Factors
Abstract

International audience; Rhabdoid tumors (RTs) are genomically simple pediatric cancers driven by the biallelic inactivation of SMARCB1, leading to SWI/SNF chromatin remodeler complex deficiency. Comprehensive evaluation of the immune infiltrates of human and mice RTs, including immunohistochemistry, bulk RNA sequencing and DNA methylation profiling studies showed a high rate of tumors infiltrated by T and myeloid cells. Single-cell RNA (scRNA) and T cell receptor sequencing highlighted the heterogeneity of these cells and revealed therapeutically targetable exhausted effector and clonally expanded tissue resident memory CD8+ T subpopulations, likely representing tumor-specific cells. Checkpoint blockade therapy in an experimental RT model induced the regression of established tumors and durable immune responses. Finally, we show that one mechanism mediating RTs immunogenicity involves SMARCB1-dependent re-expression of endogenous retroviruses and interferon-signaling activation.

Published
2019
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10. Adhesion to nanofibers drives cell membrane remodeling through 1D wetting

Author

Valeria Manriquez, Patricia Bassereau, K Melican, Pierre Lafaye, Feng-Ching Tsai, Guillaume Duménil, Ralitza Staneva, Corinne Millien, Aurélie Bertin, Audrey Salles, Sylvie Goussard, Adeline Mallet, Matthieu Piel, Spencer L. Shorte, Daria Bonazzi, Martin Sachse, Arthur Charles-Orszag, Françoise Brochard-Wyart, and Jacomina Krijnse-Locker

Subjects
Endothelial stem cell, Cell membrane, Membrane, medicine.anatomical_structure, Chemistry, Nanofiber, Neisseria meningitidis, Biophysics, medicine, Extracellular, Wetting, Adhesion, medicine.disease_cause
Abstract

The shape of cellular membranes is highly regulated by a set of conserved mechanisms. These mechanisms can be manipulated by bacterial pathogens to infect cells. Human endothelial cell plasma membrane remodeling by the bacteriumNeisseria meningitidisis thought to be essential during the blood phase of meningococcal infection, but the underlying mechanisms are unknown. Here we show that plasma membrane remodeling occurs independently of F-actin, along meningococcal type IV pili fibers, by a novel physical mechanism we term “ onedimensional” membrane wetting. We provide a theoretical model that gives the physical basis of 1D wetting and show that this mechanism occurs in model membranes interacting with model nanofibers, and in human cells interacting with model extracellular matrices. It is thus a new general principle driving the interaction of cells with their environment at the nanoscale that is diverted by meningococcus during infection.

Published
2018
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11. Intermittent pili-mediated forces fluidize Neisseria meningitidis aggregates promoting vascular colonization

Author

Valeria Manriquez, Pierre Nivoit, Guillaume Duménil, Valentina Lo Schiavo, Hirokazu Tanimoto, Silke Machata, Julien Husson, Raphaël Voituriez, Daria Bonazzi, Hugues Chaté, Nelly Henry, Ilyas Djafer-Cherif, GIRARD, Dominique, Programme interdiciplinaire en physique et chimie du vivant - Infections de la circulation sanguine : nouveaux modèles expérimentaux intégrant leur environnement mécanique spécifique - - BUGS-IN-FLOW2008 - ANR-08-PCVI-0032 - PCV - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Pathogénèse des Infections vasculaires / Pathogenesis of Vascular Infections, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Systèmes Physiques Hors-équilibre, hYdrodynamique, éNergie et compleXes (SPHYNX), Service de physique de l'état condensé (SPEC - UMR3680), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut Rayonnement Matière de Saclay (IRAMIS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'hydrodynamique (LadHyX), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Jean Perrin (LJP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Beijing Computational Science Research Center [Beijing] (CSRC), Laboratoire de Physique Théorique de la Matière Condensée (LPTMC), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Agence National de la Recherche (ANR-08-PCVI-0032, G.D.), the Fondation pour la Recherche Médicale (DEI20151234399, G.D. and H.C.), the Integrative Biology of Emerging Infectious Diseases (IBEID) laboratory of excellence (ANR-10-LABX-62), and a VIP European Research Councilstarting grant (310790-VIP, G.D.). D.B. was funded by the 2015 Roux-Cantarini fellowship (Institut Pasteur) and the 2017 Lefoulon-Delalande fellowship (Collège de France)., ANR-08-PCVI-0032,BUGS-IN-FLOW,Infections de la circulation sanguine : nouveaux modèles expérimentaux intégrant leur environnement mécanique spécifique(2008), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Male, 030106 microbiology, Transplantation, Heterologous, Mice, SCID, Neisseria meningitidis, medicine.disease_cause, Time-Lapse Imaging, General Biochemistry, Genetics and Molecular Biology, Pilus, Bacterial Adhesion, [PHYS] Physics [physics], Blood capillary, blood vessels, 03 medical and health sciences, Mice, biophysics, medicine, Human Umbilical Vein Endothelial Cells, Animals, Humans, Surface Tension, Colonization, Endothelium, bacteria, [PHYS]Physics [physics], Microscopy, Confocal, biology, type IV pili, aggregation, meningitis, Skin Transplantation, biology.organism_classification, Bacterial Load, infection, Active matter, Capillaries, 030104 developmental biology, Fimbriae, Bacterial, Biophysics, Female, Fimbriae Proteins, active matter, Bacteria
Abstract

International audience; Neisseria meningitidis, a bacterium responsible for meningitis and septicemia, proliferates and eventually fills the lumen of blood capillaries with multicellular aggregates. The impact of this aggregation process and its specific properties are unknown. We first show that aggregative properties are necessary for efficient infection and study their underlying physical mechanisms. Micropipette aspiration and single-cell tracking unravel unique features of an atypical fluidized phase, with single-cell diffusion exceeding that of isolated cells. A quantitative description of the bacterial pair interactions combined with active matter physics-based modeling show that this behavior relies on type IV pili active dynamics that mediate alternating phases of bacteria fast mutual approach, contact, and release. These peculiar fluid properties proved necessary to adjust to the geometry of capillaries upon bacterial proliferation. Intermittent attractive forces thus generate a fluidized phase that allows for efficient colonization of the blood capillary network during infection.

Published
2018
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12. Trichostatin A Promotes the Generation and Suppressive Functions of Regulatory T Cells

Author

Cristian Doñas, Macarena Fritz, Valeria Manríquez, Gabriela Tejón, María Rosa Bono, Alejandra Loyola, and Mario Rosemblatt

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Regulatory T cells are a specific subset of lymphocytes that suppress immune responses and play a crucial role in the maintenance of self-tolerance. They can be generated in the thymus as well as in the periphery through differentiation of naïve CD4+ T cells. The forkhead box P3 transcription factor (Foxp3) is a crucial molecule regulating the generation and function of Tregs. Here we show that the foxp3 gene promoter becomes hyperacetylated in in vitro differentiated Tregs compared to naïve CD4+ T cells. We also show that the histone deacetylase inhibitor TSA stimulated the in vitro differentiation of naïve CD4+ T cells into Tregs and that this induction was accompanied by a global increase in histone H3 acetylation. Importantly, we also demonstrated that Tregs generated in the presence of TSA have phenotypical and functional differences from the Tregs generated in the absence of TSA. Thus, TSA-generated Tregs showed increased suppressive activities, which could potentially be explained by a mechanism involving the ectonucleotidases CD39 and CD73. Our data show that TSA could potentially be used to enhance the differentiation and suppressive function of CD4+Foxp3+ Treg cells.

Published
2013
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