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251 results on '"Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)"'

1. Towards the Clinical Application of Gene Therapy for Genetic Inner Ear Diseases

Author: Ghizlene Lahlou, Charlotte Calvet, Marie Giorgi, Marie-José Lecomte, Saaid Safieddine, Technologies et thérapie génique pour la surdité - Technologies and Gene Therapy for Deafness (TGTD), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Zürich [Zürich] = University of Zurich (UZH), This work was supported by Fondation pour l’Audition (FPA IDA08 to S.S.), RHU AUDINNOVE (ANR-18-RHUS-0007 to S.S.), and the Scholarship CRS Amplifon 2018., and ANR-18-RHUS-0007,AUDINNOVE,Treating congenital hearing impairment(2018)
Subjects: vestibular defect, [SDV]Life Sciences [q-bio], AAV, General Medicine, hearing impairment, gene therapy
Abstract: Hearing loss, the most common human sensory defect worldwide, is a major public health problem. About 70% of congenital forms and 25% of adult-onset forms of deafness are of genetic origin. In total, 136 deafness genes have already been identified and there are thought to be several hundred more awaiting identification. However, there is currently no cure for sensorineural deafness. In recent years, translational research studies have shown gene therapy to be effective against inherited inner ear diseases, and the application of this technology to humans is now within reach. We provide here a comprehensive and practical overview of current advances in gene therapy for inherited deafness, with and without an associated vestibular defect. We focus on the different gene therapy approaches, considering their prospects, including the viral vector used, and the delivery route. We also discuss the clinical application of the various strategies, their strengths, weaknesses, and the challenges to be overcome.
Published: 2023

2. Usher syndrome Recent advances in our understanding of genes and therapeutics

Author: El-Amraoui, Aziz, Géléoc, Gwenaelle, Déficits Sensoriels Progressifs, Pathophysiologie et Thérapie / Progressive Sensory Disorders, Pathophysiology and Therapy (DSP), Sorbonne Université (SU)-Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Harvard Medical School [Boston] (HMS), French National Research Agency (ANR)-HearInNoise (ANR-17-CE16-0017), EuroNanoMed-NanoEar (ANR-21-ENM3-0003-04), and Fondation pour l’Audition (FPA-19-Stg), The Usher Syndrome Society, The Barber Gene Therapy Fund, ANR-17-CE16-0017,HearInNoise,Surdité d'apparition tardive et progressive: de la physiopathologie à la thérapie(2017), and ANR-21-ENM3-0003,NANOEAR,New DX243-conjugated nanoparticles as a neuroprotective drug for hearing loss(2021)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; Usher syndrome is a rare disease that affects the sensory systems of vision, hearing, and balance. Recent advances in scientific technologies reveal the genes involved in Usher syndrome, their varying phenotypic outcomes, and avenues for therapeutic development. Dr Aziz El-Amraoui of the Pasteur Institute in Paris, France, and Dr Gwenaelle Géléoc of Boston Children’s Hospital and Harvard Medical School in the US, review these advances in our understanding of disease pathogenesis and therapeutic developments. They take stock of the current situation, discuss the need for revised diagnostic guidelines, and frame the future of research in this field.
Published: 2022

3. Otology and audiology, a rapidly changing care pathway inspired by scientific breakthroughs [Editorial]

Author: Paul, Avan, Christine, Petit, Université Clermont Auvergne (UCA), Centre de recherche et innovation en audiologie humaine / Center for Research and Innovation in Human Audiology (CERIAH), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Collège de France (CdF (institution))
Subjects: Otolaryngology, MESH: Humans, MESH: Audiology, [SDV]Life Sciences [q-bio], Critical Pathways, Humans, Audiology, MESH: Critical Pathways, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, MESH: Otolaryngology
Abstract: International audience
Published: 2022

4. Déficience auditive induite par le bruit : comment peut-elle être prévenue et traitée ?

Author: Delmaghani, Sedigheh, El-Amraoui, Aziz, Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Déficits Sensoriels Progressifs, Pathophysiologie et Thérapie / Progressive Sensory Disorders, Pathophysiology and Therapy (DSP), Sorbonne Université (SU)-Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and EL-AMRAOUI, Aziz
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract: National audience; Selon l’Organisation mondiale de la santé, 466 millions d'individus dont 34 millions d’enfants présentent une déficience auditive handicapante, et un milliard de personnes seront touchées en 2050. Ces atteintes ont des causes multiples, peuvent survenir à tout âge et avoir des degrés de sévérité et de progression variables. Notre environnement devenant de plus en plus bruyant, les sources de nuisances sonores allant croissantes, l’exposition au bruit occupe malheureusement une place de plus en plus importante comme cause de perte d'audition. Bien qu’évitables, ces atteintes ont un impact économique et sociétal très important. En effet, l’exposition prolongée au bruit ou à des sons de forte intensité peut entraîner des dommages irréversibles aux cellules sensorielles et aux neurones auditifs, ce qui détériore la perception auditive et perturbe l’intelligibilité de la parole.
Published: 2022

5. Prevalence of Hearing Loss and Hearing Aid Use Among Adults in France in the CONSTANCES Study

Author: Quentin Lisan, Marcel Goldberg, Ghizlene Lahlou, Anna Ozguler, Sylvie Lemonnier, Xavier Jouven, Marie Zins, Jean-Philippe Empana, Hôpital Foch [Suresnes], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), UMS 011, Institut National de la Santé et de la Recherche Médicale (INSERM), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Université Paris Cité (UPCité), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Technologies et thérapie génique pour la surdité - Technologies and Gene Therapy for Deafness (TGTD), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de cardiologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), The CONSTANCES cohort study was funded by the Caisse Nationale d’Assurance Maladie (CNAM), the Ministry of Health, the Council of the Ile de France Region, and the Cohorts TGIR IReSP-ISP INSERM (Ministère de la santé et des sports, Ministère délégué à la recherche, Institut national de la santé et de la recherche médicale, Institut national du cancer et Caisse nationale de solidarité pour l’autonomie). The CONSTANCES cohort study is an Infrastructure nationale en Biologie et Santé and benefits from a grant from the Agence Nationale de la Recherche (ANR-11-INBS-0002)., and ANR-11-INBS-0002,CONSTANCES,La cohorte CONSTANCES - Infrastructure épidémiologique ouverte pour la recherche et la surveillance(2011)
Subjects: Adult, Male, Adolescent, [SDV]Life Sciences [q-bio], MESH: Deafness, Deafness, MESH: Hearing Aids, Cohort Studies, Young Adult, Hearing Aids, MESH: Cross-Sectional Studies, Prevalence, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Hearing Loss, MESH: Hearing Loss, MESH: Cohort Studies, MESH: Prevalence, Aged, MESH: Adolescent, MESH: Aged, MESH: Humans, MESH: Middle Aged, MESH: Adult, General Medicine, Middle Aged, MESH: Male, Cross-Sectional Studies, MESH: Young Adult, Female, MESH: Female
Abstract: International audience; Importance Although hearing loss is common in the population worldwide, the prevalence of hearing loss and hearing aid use is not known.Objective To estimate the prevalence of hearing loss and hearing aid use in the adult French population.Design, Setting, and Participants This cohort study used data from the CONSTANCES cohort, a representative sample of the French population. Volunteers aged 18 to 75 years were recruited at 21 preventive health centers between January 1, 2012, and December 31, 2019. The present study included participants with audiometric data.Main Outcomes and Measures The main outcomes were prevalence of hearing loss and disabling hearing loss overall and by sex and age group and prevalence of self-reported hearing aid use among those with disabling hearing loss. Hearing loss was defined as a pure-tone average (PTA) in the better ear of 20 dB or higher, and disabling hearing loss was defined as a PTA in the better ear of 35 dB or higher.Results Of 200 870 participants in the CONSTANCES study, 186 460 had full audiometric data and were included in this study (mean [SD] age, 47.1 [13.5] years); 100 330 (53.8%) were female, and 86 130 (46.2%) were male. Of these participants, 24.8% (95% CI, 24.6%-25.0%) had hearing loss and 4.3% (95% CI, 4.2%-4.4%) had disabling hearing loss. The prevalence rates of hearing loss increased from 3.4% (95% CI, 2.8%-3.9%) at age 18 to 25 years to 73.3% (95% CI, 69.5%-77.2%) at age 71 to 75 years among men and from 4.4% (95% CI, 3.9%-5.0%) at age 18 to 25 years to 64.1% (95% CI, 59.7%-68.4%) at age 71 to 75 years among women. The prevalence of disabling hearing loss increased from 0.3% (95% CI, 0.2%-0.4%) among participants aged 18 to 25 years to 23.3% (95% CI, 20.7%-26.0%) among participants aged 71 to 75 years. Among the 8050 participants with disabling hearing loss, 36.8% (95% CI, 35.8%-37.9%) reported using hearing aids, including 56.7% (95% CI, 38.9%-74.4%) aged 18 to 25 years and 32.9% (95% CI, 26.8%-39.2%) aged 71 to 75 years.Conclusions and Relevance In this cohort study, hearing loss was prevalent in France, and the prevalence of hearing loss increased with age among both men and women. Hearing aids were underused, particularly among older individuals. These findings suggest that hearing loss prevention and screening in the French population are needed.
Published: 2022

6. Best Fit 3D Basilar Membrane Reconstruction to Routinely Assess the Scalar Position of the Electrode Array after Cochlear Implantation

Author: Renato Torres, Jean-Yves Tinevez, Hannah Daoudi, Ghizlene Lahlou, Neil Grislain, Eugénie Breil, Olivier Sterkers, Isabelle Mosnier, Yann Nguyen, Evelyne Ferrary, Technologies et thérapie génique pour la surdité - Technologies and Gene Therapy for Deafness (TGTD), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universidad Nacional de San Agustín (UNSA), Hub d'analyse d'images - Image Analysis Hub (Platform) (IAH), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), This research was funded by the Fondation pour l’Audition (Starting Grant IDA-2020), ANR Robocop ANR-19-CE19-0026-02., ANR-19-CE19-0026,ROBOCOP,robotisation de l'implant cochléaire(2019), Tinevez, Jean-Yves, and robotisation de l'implant cochléaire - - ROBOCOP2019 - ANR-19-CE19-0026 - AAPG2019 - VALID
Subjects: [SDV] Life Sciences [q-bio], auditory prosthesis, [SDV]Life Sciences [q-bio], hearing impairment rehabilitation, scala tympani, otorhinolaryngologic diseases, electrode array translocation, General Medicine, sense organs, hearing loss, scala vestibuli
Abstract: International audience; The scalar position of the electrode array is assumed to be associated with auditory performance after cochlear implantation. We propose a new method that can be routinely applied in clinical practice to assess the position of an electrode array. Ten basilar membrane templates were generated using micro-computed tomography (micro-CT), based on the dimensions of 100 cochleae. Five surgeons were blinded to determine the position of the electrode array in 30 cadaveric cochleae. The procedure consisted of selecting the appropriate template based on cochlear dimensions, merging the electrode array reconstruction with the template using four landmarks, determining the position of the array according to the template position, and comparing the results obtained to histology data. The time taken to analyze each implanted cochlea was approximately 12 min. We found that, according to histology, surgeons were in almost perfect agreement when determining an electrode translocated to the scala vestibuli with the perimodiolar MidScala array (Fleiss’ kappa (κ) = 0.82), and in moderate agreement when using the lateral wall EVO array (κ = 0.42). Our data indicate that an adapted basilar membrane template can be used as a rapid and reproducible method to assess the position of the electrode array after cochlear implantation.
Published: 2022
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7. Antibiotics in mastoid and epitympanic obliteration with S53P4 bioactive glass: A retrospective study

Author: Lauranne Alciato, Daniele Bernardeschi, Valérie Pourcher, Naira Mkrtchyan, Frédéric Tankéré, Olivier Sterkers, Ghizlène Lahlou, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Centre National de la Recherche Scientifique (CNRS), Technologies et thérapie génique pour la surdité - Technologies and Gene Therapy for Deafness (TGTD), Institut de l'Audition [Paris] (IDA), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: antibiotic resistance, chronic otitis media, middle ear, [SDV]Life Sciences [q-bio], General Medicine, surgical site infection, cholesteatoma
Abstract: International audience; Objective: The role of antibiotics in ear surgery is still controversial. The aim of this study was to assess their need in cholesteatoma surgery when performing obliteration with S53P4 bioactive glass, a biocompatible material with antibacterial properties. Methods: This retrospective cohort study was conducted in a tertiary referral center between January 2017 and May 2019. Sixty-nine consecutive patients, who underwent surgery for cholesteatoma removal and/or rehabilitation of canal-wall-down mastoidectomy with mastoid and epitympanic obliteration using S53P4 granules were included. Before 2019, antibiotics were routinely used (group "w/AB"). Patients received intravenous antibiotics during surgery, oral treatment was continued for 7 days and topical antibiotics for 1 month. After 2019, no antibiotics were administered (group "w/oAB"). The primary outcome was the occurrence of early surgical site infection. Secondary outcomes were late infection, anatomic and functional results at 3 and 12 months. Results: Twenty-three patients were included in group "w/oAB" and 46 in group "w/ AB", with no significant differences in demographics, medical history or follow-up. Five ears (22%) in group "w/oAB" developed an early infection compared with 2 (4%) in group "w/AB" (p = .03). The relative risk was 6.11, 95CI%[1.09;31.96]. Infections were successfully treated with antibiotics, and no patient underwent surgical removal of the granules. No late infections or complications were observed. There was no difference in graft failure or air-bone gap closure at 1 year. Conclusion: Peri-/post-operative antibiotics prevent early infection in obliteration surgery with S53P4 granules. Infections can be treated medically without complications or require removal of the implanted material.
Published: 2022

8. The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification

Author: Sedigheh Delmaghani, Aziz EL-AMRAOUI, Déficits Sensoriels Progressifs, Pathophysiologie et Thérapie / Progressive Sensory Disorders, Pathophysiology and Therapy (DSP), Sorbonne Université (SU)-Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), The work in the authors’ laboratories was funded by the French National Research Agency (ANR), as part of the second 'Investissements d’Avenir' program (light4deaf, ANR-15-RHUS-0001), and LabEx LIFESENSES (ANR-10-LABX-65), ANR-HearInNoise (ANR-17-CE16-0017), EuroNanoMed-NanoEar (ANR-21-ENM3-0003-04), LHW-Stiftung, Fondation de France, Fondation Maladies Rares, Retina-France, and Fondation pour l’Audition (FPA-19-Stg)., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE(2010), ANR-17-CE16-0017,HearInNoise,Surdité d'apparition tardive et progressive: de la physiopathologie à la thérapie(2017), ANR-21-ENM3-0003,NANOEAR,New DX243-conjugated nanoparticles as a neuroprotective drug for hearing loss(2021), EL-AMRAOUI, Aziz, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, DES SENS POUR TOUTE LA VIE - - LIFESENSES2010 - ANR-10-LABX-0065 - LABX - VALID, Surdité d'apparition tardive et progressive: de la physiopathologie à la thérapie - - HearInNoise2017 - ANR-17-CE16-0017 - AAPG2017 - VALID, and New DX243-conjugated nanoparticles as a neuroprotective drug for hearing loss - - NANOEAR2021 - ANR-21-ENM3-0003 - EuroNanoMed III - VALID
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], Mutation, otorhinolaryngologic diseases, Genetics, Humans, Usher Syndromes, Genetics (clinical), Genetic Association Studies
Abstract: Usher syndrome (USH) is the most common cause of deaf–blindness in humans, with a prevalence of about 1/10,000 (~ 400,000 people worldwide). Cochlear implants are currently used to reduce the burden of hearing loss in severe-to-profoundly deaf patients, but many promising treatments including gene, cell, and drug therapies to restore the native function of the inner ear and retinal sensory cells are under investigation. The traditional clinical classification of Usher syndrome defines three major subtypes—USH1, 2 and 3—according to hearing loss severity and onset, the presence or absence of vestibular dysfunction, and age at onset of retinitis pigmentosa. Pathogenic variants of nine USH genes have been initially reported: MYO7A, USH1C, PCDH15, CDH23, and USH1G for USH1, USH2A, ADGRV1, and WHRN for USH2, and CLRN1 for USH3. Based on the co-occurrence of hearing and vision deficits, the list of USH genes has been extended to few other genes, but with limited supporting information. A consensus on combined criteria for Usher syndrome is crucial for the development of accurate diagnosis and to improve patient management. In recent years, a wealth of information has been obtained concerning the properties of the Usher proteins, related molecular networks, potential genotype–phenotype correlations, and the pathogenic mechanisms underlying the impairment or loss of hearing, balance and vision. The advent of precision medicine calls for a clear and more precise diagnosis of Usher syndrome, exploiting all the existing data to develop a combined clinical/genetic/network/functional classification for Usher syndrome.
Published: 2022

9. Olfactory function in congenital cytomegalovirus infection: a prospective study

Author: Françoise Lazarini, Sarah Levivien, Yoann Madec, Fabien Taieb, Estelle Mottez, Tan-Phuc Buivan, Audrey Maudoux, Sylvette Wiener-Vacher, Jérôme Nevoux, Thierry Van Den Abbeele, Pierre Gressens, Pierre-Marie Lledo, Natacha Teissier, Lazarini, Françoise, Perception et Mémoire / Perception and Memory, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Université Paris Cité (UPCité)-Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Pôle Intégré de Recherche Clinique (PIRC), Déficits Sensoriels Progressifs, Pathophysiologie et Thérapie / Progressive Sensory Disorders, Pathophysiology and Therapy (DSP), Sorbonne Université (SU)-Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), This study was supported by Institut Pasteur of Paris (GPF 2015 Microbes and Brain 'INFECSMELL'), Inserm, and Université de Paris and sponsored by Institut Pasteur of Paris (2015–091)., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris]-Université Paris Cité (UPCité), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: Male, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Infant, Newborn, Olfaction, Odorant mixture, Smell, Child, Preschool, Cytomegalovirus Infections, Pediatrics, Perinatology and Child Health, Diagnosis, Discrimination, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Humans, Female, Original Article, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Prospective Studies, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Child, Children
Abstract: Congenital cytomegalovirus (CMV) infection leads to olfactory bulb lesions in the fetus, yet little is known about its impact on olfaction after birth. Here, we have assessed in a prospective study conducted on children in two French hospitals from 2016 to 2019, infection severity and olfactory performance after congenital CMV infection. Children with congenital CMV infection aged 3 to 10 years and healthy controls (CTL) matched for age and sex to CMV children symptomatic at birth (sCMV) were enrolled. Olfactory discrimination was assessed using mono-odorants and binary mixtures. Data were analyzed for 54 children with PCR-confirmed congenital CMV infection, including 34 sCMV (median [IQR] age, 6 [5–8] years; 19 [55.9%] male), and 20 CMV asymptomatic at birth (aCMV, median [IQR] age, 4 [3–6] years; 12 [60.0%] male). sCMV were compared to 34 CTL children. Olfactory scores in CMV-infected children were independent from vestibular deficit and hearing loss. The olfactory score was efficient to discriminate between CTL and sCMV for children > 6 years (area under the receiver-operating characteristic curve (AUC, 0.85; P = 0.0006), but not for children 6 years, the proportion of children with total olfactory score
Published: 2022

10. Vestibular Deficits in Deafness: Clinical Presentation, Animal Modeling, and Treatment Solutions

Author: Audrey Maudoux, Sandrine Vitry, Aziz El-Amraoui, Déficits Sensoriels Progressifs, Pathophysiologie et Thérapie / Progressive Sensory Disorders, Pathophysiology and Therapy (DSP), Sorbonne Université (SU)-Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris] (IP), The work in the authors' laboratories was funded by the French National Research Agency (ANR), as part of the Second Investissements d'Avenir Program (light4deaf, ANR-15-RHUS-0001), and LabEx LIFESENSES (ANR-10-LABX-65), Fondation pour l'Audition (FPA-19-Stg), ANR-HearInNoise-(ANR-17-CE16-0017), LHW-Stiftung, Fondation de France, Fondation Maladies Rares, & Retina-France. We acknowledge the support of the Institut de l‘Audition by Fondation pour l'Audition, We thank Pr. Anna Lysakowski for critical review of the manuscript, and her helpful comments and suggestions, ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE(2010), ANR-17-CE16-0017,HearInNoise,Surdité d'apparition tardive et progressive: de la physiopathologie à la thérapie(2017), VITRY, Sandrine, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, DES SENS POUR TOUTE LA VIE - - LIFESENSES2010 - ANR-10-LABX-0065 - LABX - VALID, and Surdité d'apparition tardive et progressive: de la physiopathologie à la thérapie - - HearInNoise2017 - ANR-17-CE16-0017 - AAPG2017 - VALID
Subjects: [SDV] Life Sciences [q-bio], Neurology, deafness, vestibulopathy, [SDV]Life Sciences [q-bio], balance disorders, otorhinolaryngologic diseases, rare diseases, sense organs, Neurology (clinical), pathophysiology and gene therapy, animal models
Abstract: International audience; The inner ear is responsible for both hearing and balance. These functions are dependent on the correct functioning of mechanosensitive hair cells, which convert sound- and motion-induced stimuli into electrical signals conveyed to the brain. During evolution of the inner ear, the major changes occurred in the hearing organ, whereas the structure of the vestibular organs remained constant in all vertebrates over the same period. Vestibular deficits are highly prevalent in humans, due to multiple intersecting causes: genetics, environmental factors, ototoxic drugs, infections and aging. Studies of deafness genes associated with balance deficits and their corresponding animal models have shed light on the development and function of these two sensory systems. Bilateral vestibular deficits often impair individual postural control, gaze stabilization, locomotion and spatial orientation. The resulting dizziness, vertigo, and/or falls (frequent in elderly populations) greatly affect patient quality of life. In the absence of treatment, prosthetic devices, such as vestibular implants, providing information about the direction, amplitude and velocity of body movements, are being developed and have given promising results in animal models and humans. Novel methods and techniques have led to major progress in gene therapies targeting the inner ear (gene supplementation and gene editing), 3D inner ear organoids and reprograming protocols for generating hair cell-like cells. These rapid advances in multiscale approaches covering basic research, clinical diagnostics and therapies are fostering interdisciplinary research to develop personalized treatments for vestibular disorders.
Published: 2021

11. Implication of Vestibular Hair Cell Loss of Planar Polarity for the Canal and Otolith-Dependent Vestibulo-Ocular Reflexes in Celsr1–/– Mice

Author: François Simon, Fadel Tissir, Vincent Michel, Ghizlene Lahlou, Michael Deans, Mathieu Beraneck, Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Catholique de Louvain = Catholic University of Louvain (UCL), Hamad Bin Khalifa University (HBKU), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Technologies et thérapie génique pour la surdité - Technologies and Gene Therapy for Deafness (TGTD), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Utah School of Medicine [Salt Lake City], This work was supported by the Centre National d’Etudes Spatiales, the Centre National de la Recherche Scientifique, and the Université de Paris. This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001. This work has benefited from the support and expertise of the animal facility of BioMedTech Facilities at Université de Paris (Institut National de la Santé et de la Recherche Médicale Unité S36/Unité Mixte de Service 2009). MB and FS received support from Marc Boulet Audition., ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Oto-Rhino-Laryngologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), HAL-SU, Gestionnaire, and Université de Paris - - Université de Paris2018 - ANR-18-IDEX-0001 - IDEX - VALID
Subjects: genetic structures, mouse model, [SDV]Life Sciences [q-bio], Neurosciences. Biological psychiatry. Neuropsychiatry, Biology, vestibulo ocular reflex, CELSR1, hair cell, 03 medical and health sciences, 0302 clinical medicine, medicine, otorhinolaryngologic diseases, Vestibular Hair Cell, 030304 developmental biology, Otolith, Vestibular system, 0303 health sciences, Semicircular canal, General Neuroscience, vestibular system, Anatomy, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Reflex, Hair cell, sense organs, Vestibulo–ocular reflex, Transduction (physiology), 030217 neurology & neurosurgery, planar cell polarity (PCP), RC321-571
Abstract: Introduction: Vestibular sensory hair cells are precisely orientated according to planar cell polarity (PCP) and are key to enable mechanic-electrical transduction and normal vestibular function. PCP is found on different scales in the vestibular organs, ranging from correct hair bundle orientation, coordination of hair cell orientation with neighboring hair cells, and orientation around the striola in otolithic organs. Celsr1 is a PCP protein and a Celsr1 KO mouse model showed hair cell disorganization in all vestibular organs, especially in the canalar ampullae. The objective of this work was to assess to what extent the different vestibulo-ocular reflexes were impaired in Celsr1 KO mice.Methods: Vestibular function was analyzed using non-invasive video-oculography. Semicircular canal function was assessed during sinusoidal rotation and during angular velocity steps. Otolithic function (mainly utricular) was assessed during off-vertical axis rotation (OVAR) and during static and dynamic head tilts.Results: The vestibulo-ocular reflex of 10 Celsr1 KO and 10 control littermates was analyzed. All KO mice presented with spontaneous nystagmus or gaze instability in dark. Canalar function was reduced almost by half in KO mice. Compared to control mice, KO mice had reduced angular VOR gain in all tested frequencies (0.2–1.5 Hz), and abnormal phase at 0.2 and 0.5 Hz. Concerning horizontal steps, KO mice had reduced responses. Otolithic function was reduced by about a third in KO mice. Static ocular-counter roll gain and OVAR bias were both significantly reduced. These results demonstrate that canal- and otolith-dependent vestibulo-ocular reflexes are impaired in KO mice.Conclusion: The major ampullar disorganization led to an important reduction but not to a complete loss of angular coding capacities. Mildly disorganized otolithic hair cells were associated with a significant loss of otolith-dependent function. These results suggest that the highly organized polarization of otolithic hair cells is a critical factor for the accurate encoding of the head movement and that the loss of a small fraction of the otolithic hair cells in pathological conditions is likely to have major functional consequences. Altogether, these results shed light on how partial loss of vestibular information encoding, as often encountered in pathological situations, translates into functional deficits.
Published: 2021

12. Review of Genotype-Phenotype Correlations in Usher Syndrome

Author: Susan H. Blanton, Eric Nisenbaum, Xuezhong Liu, Byron L. Lam, Denise Yan, Torin P Thielhelm, Karl R. Koehler, Aziz El-Amraoui, Aida Nourbakhsh, Zheng-Yi Chen, Yilai Shu, University of Miami Leonard M. Miller School of Medicine (UMMSM), Fudan University [Shanghai], Harvard Medical School [Boston] (HMS), Déficits Sensoriels Progressifs, Pathophysiologie et Thérapie / Progressive Sensory Disorders, Pathophysiology and Therapy (DSP), Sorbonne Université (SU)-Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Dr. Liu’s lab is supported by NIH grants of R01DC005575, R01DC012115. Drs. Eric Nisenbaum and Aida Nourbakhsh are supported by T32 DC015995.
Subjects: Genetics, Mutation, Usher syndrome, Disease, Biology, medicine.disease, medicine.disease_cause, Phenotype, Article, Speech and Hearing, Otorhinolaryngology, otorhinolaryngologic diseases, medicine, Humans, Sensorineural hearing loss, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Allele, Age of onset, Gene, Usher Syndromes, Genetic Association Studies
Abstract: International audience; Usher syndrome (USH) encompasses a group of clinically and genetically heterogenous disorders defined by the triad of sensorineural hearing loss (SNHL), vestibular dysfunction, and vision loss. USH is the most common cause of deaf blindness. USH is divided clinically into three subtypes—USH1, USH2, and USH3—based on symptom severity, progression, and age of onset. The underlying genetics of these USH forms are, however, significantly more complex, with over a dozen genes linked to the three primary clinical subtypes and other atypical USH phenotypes. Several of these genes are associated with other deaf-blindness syndromes that share significant clinical overlap with USH, pointing to the limits of a clinically based classification system. The genotype-phenotype relationships among USH forms also may vary significantly based on the location and type of mutation in the gene of interest. Understanding these genotype-phenotype relationships and associated natural disease histories is necessary for the successful development and application of gene-based therapies and precision medicine approaches to USH. Currently, the state of knowledge varies widely depending on the gene of interest. Recent studies utilizing next-generation sequencing technology have expanded the list of known pathogenic mutations in USH genes, identified new genes associated with USH-like phenotypes, and proposed algorithms to predict the phenotypic effects of specific categories of allelic variants. Further work is required to validate USH gene causality, and better define USH genotype-phenotype relationships and disease natural histories—particularly for rare mutations—to lay the groundwork for the future of USH treatment.
Published: 2021

13. Different CaV1.3 Channel Isoforms Control Distinct Components of the Synaptic Vesicle Cycle in Auditory Inner Hair Cells

Author: Didier Dulon, Philippe F.Y. Vincent, Yohan Bouleau, Gilles Charpentier, Saaid Safieddine, Alice Emptoz, Christine Petit, Neurophysiologie de la synapse auditive - Clinical and translational exploration of sensorineural hearing loss, Université de Bordeaux Ségalen [Bordeaux 2]-Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Génétique et Physiologie de l'Audition, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), and This work was supported by the Fondation Agir Pour l’Audition (2015-APA Research Grant 'Deciphering the role of otoferlin and Usher proteins at the auditory hair cell ribbon synapse' to D.D.).
Subjects: 0301 basic medicine, medicine.medical_specialty, hair cells, Biology, Ribbon synapse, Exocytosis, 03 medical and health sciences, chemistry.chemical_compound, Nifedipine, calcium channels, Internal medicine, medicine, Channel blocker, auditory, Voltage-dependent calcium channel, General Neuroscience, Synaptic vesicle cycle, Cell biology, EGTA, 030104 developmental biology, Endocrinology, chemistry, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Intracellular, synaptic exocytosis, medicine.drug
Abstract: The mechanisms orchestrating transient and sustained exocytosis in auditory inner hair cells (IHCs) remain largely unknown. These exocytotic responses are believed to mobilize sequentially a readily releasable pool of vesicles (RRP) underneath the synaptic ribbons and a slowly releasable pool of vesicles (SRP) at farther distance from them. They are both governed by Cav1.3 channels and require otoferlin as Ca2+sensor, but whether they use the same Cav1.3 isoforms is still unknown. Using whole-cell patch-clamp recordings in posthearing mice, we show that only a proportion (∼25%) of the total Ca2+current in IHCs displaying fast inactivation and resistance to 20 μmnifedipine, al-type Ca2+channel blocker, is sufficient to trigger RRP but not SRP exocytosis. This Ca2+current is likely conducted by short C-terminal isoforms of Cav1.3 channels, notably Cav1.342Aand Cav1.343S, because their mRNA is highly expressed in wild-type IHCs but poorly expressed inOtof−/−IHCs, the latter having Ca2+currents with considerably reduced inactivation. Nifedipine-resistant RRP exocytosis was poorly affected by 5 mmintracellular EGTA, suggesting that the Cav1.3 short isoforms are closely associated with the release site at the synaptic ribbons. Conversely, our results suggest that Cav1.3 long isoforms, which carry ∼75% of the total IHC Ca2+current with slow inactivation and confer high sensitivity to nifedipine and to internal EGTA, are essentially involved in recruiting SRP vesicles. Intracellular Ca2+imaging showed that Cav1.3 long isoforms support a deep intracellular diffusion of Ca2+.SIGNIFICANCE STATEMENTAuditory inner hair cells (IHCs) encode sounds into nerve impulses through fast and indefatigable Ca2+-dependent exocytosis at their ribbon synapses. We show that this synaptic process involves long and short C-terminal isoforms of the Cav1.3 Ca2+channel that differ in the kinetics of their Ca2+-dependent inactivation and their relative sensitivity to thel-type Ca2+channel blocker nifedipine. The short C-terminal isoforms, having fast inactivation and low sensitivity to nifedipine, mainly control the fast fusion of the readily releasable pool (RRP); that is, they encode the phasic exocytotic component. The long isoforms, with slow inactivation and great sensitivity to nifedipine, mainly regulate the vesicular replenishment of the RRP; that is, the sustained or tonic exocytosis.
Published: 2017

14. What is the Functional Role of iEEG Oscillations in Neural Processing and Cognitive Functions?

Author: Proix, Timothée, Mégevand, Pierre, Giraud, Anne-Lise, Department of Basic Neuroscience, Université de Genève = University of Geneva (UNIGE), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Nikolai Axmacher
Subjects: [SCCO.NEUR]Cognitive science/Neuroscience, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences
Abstract: International audience; Oscillations of the electric field generated by neuronal populations are often observed in intracranial EEG recordings from human cortical and subcortical brain regions. The functional relevance of these oscillations for neural processing and cognitive functions remains a debated issue in modern neuroscience. In this chapter, we review evidence that iEEG oscillations constitute a key mechanism in the functional integration of neuronal activity across temporal and spatial scales. We focus on the potential role of cortical oscillations in cognitive processes, and particularly speech perception and production, which involve diverse brain regions and temporal scales in a structured hierarchy, as an ideal testbed for outlining the possible insights that iEEG oscillations offer on cognitive functions.
Published: 2023

15. Variants with the N501Y mutation extend SARS-CoV-2 host range to mice, with contact transmission

Author: Sylvie Behillil, Dominique Rousset, Flora Donati, Laurine Levillayer, Grégory Jouvion, Jean Jaubert, Xavier Montagutelli, Vincent Enouf, Mélanie Albert, Sylvie van der Werf, Fabiana Gámbaro, Eduard Baquero Salazar, Etienne Simon-Loriere, Félix A. Rey, Laurine Conquet, Matthieu Prot, Génétique de la souris - Mouse Genetics, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Virologie Structurale - Structural Virology, École nationale vétérinaire - Alfort (ENVA), Dynamic Microbiology - EA 7380 (DYNAMIC), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est (UPE)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Centre National de Référence des virus respiratoires (dont la grippe et le SARS-CoV2) [Paris] (CNR - laboratoire associé), Institut Pasteur de la Guyane, Réseau International des Instituts Pasteur (RIIP), This work was supported by the « URGENCE COVID-19 » fundraising campaign of Institut Pasteur), the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (Grant No. ANR-10-LABX-62-IBEID), the Agence Nationale de la Recherche (Grant No. ANR-20-COVI-0028-01) and the RECOVER project funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 101003589. ESL acknowledges funding from the INCEPTION programme (Investissements d’Avenir grant ANR-16-CONV-0005)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0028,HuMoCID,Développement de modèles murins de COVID-19(2020), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), and European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020)
Subjects: Infectivity, Genetics, Mutation rate, variants, reservoir, mice, Rodent, biology, Sars-CoV-2, Host (biology), [SDV]Life Sciences [q-bio], transmission, RNA, host range, Virus, biology.animal, Adaptation, Receptor
Abstract: Receptor recognition is a major determinant of viral host range, as well as infectivity and pathogenesis. Emergences have been associated with serendipitous events of adaptation upon encounters with a novel host, and the high mutation rate of RNA viruses has been proposed to explain their frequent host shifts 1. SARS-CoV-2 extensive circulation in humans has been associated with the emergence of variants, including variants of concern (VOCs) with diverse mutations in the spike and increased transmissibility or immune escape 2. Here we show that unlike the initial virus, VOCs are able to infect common laboratory mice, replicating to high titers in the lungs. This host range expansion is explained in part by the acquisition of changes at key positions of the receptor binding domain that enable binding to the mouse angiotensin-converting enzyme 2 (ACE2) cellular receptor, although differences between viral lineages suggest that other factors are involved in the capacity of SARS-CoV-2 VOCs to infect mice. This abrogation of the species barrier raises the possibility of wild rodent secondary reservoirs and provides new experimental models to study disease pathophysiology and countermeasures.
Published: 2023

16. Anti-V1/V3-glycan broadly HIV-1 neutralizing antibodies in a post-treatment controller

Author: Molinos-Albert, Luis, Baquero, Eduard, Bouvin-Pley, Mélanie, Lorin, Valerie, Charre, Caroline, Planchais, Cyril, Dimitrov, Jordan, Monceaux, Valérie, Vos, Matthijn, Group, Anrs Visconti, Hocqueloux, Laurent, Berger, Jean-Luc, Seaman, Michael, Braibant, Martine, Avettand-Fenoël, Véronique, Sáez-Cirión, Asier, Mouquet, Hugo, Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Plateforme technologique Nanoimagerie / Nanoimaging Technological Platform, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Réservoirs viraux et contrôle immunitaire / Viral reservoirs and immune control, HIV, Inflammation et persistance - HIV, Inflammation and Persistence, Hôpital La Source [Orléans] (HLSO), Centre Hospitalier Universitaire de Reims (CHU Reims), Beth Israel Deaconess Medical Center [Boston] (BIDMC), and Harvard Medical School [Boston] (HMS)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; HIV-1 broadly neutralizing antibodies (bNAbs) can decrease viremia but are usually unable to counteract autologous viruses escaping the antibody pressure. Nonetheless, bNAbs may contribute to natural HIV-1 control in individuals off antiretroviral therapy (ART). Here, we describe a bNAb B cell lineage elicited in a post-treatment controller (PTC) that exhibits broad seroneutralization and show that a representative antibody from this lineage, EPTC112, targets a quaternary epitope in the glycan-V3 loop supersite of the HIV-1 envelope glycoprotein. The cryo-EM structure of EPTC112 complexed with soluble BG505 SOSIP.664 envelope trimers revealed interactions with N301- and N156-branched N-glycans and the 324GDIR327 V3 loop motif. Although the sole contemporaneous virus circulating in this PTC was resistant to EPTC112, it was potently neutralized by autologous plasma IgG antibodies. Our findings illuminate how cross-neutralizing antibodies can alter the HIV-1 infection course in PTCs and may control viremia off-ART, supporting their role in functional HIV-1 cure strategies.
Published: 2023

17. A lentiviral vector expressing a dendritic cell-targeting multimer induces mucosal anti-mycobacterial CD4+ T-cell immunity

Author: François Anna, Jodie Lopez, Fanny Moncoq, Catherine Blanc, Pierre Authié, Amandine Noirat, Ingrid Fert, Philippe Souque, Fabien Nevo, Alexandre Pawlik, David Hardy, Sophie Goyard, Denis Hudrisier, Roland Brosch, Françoise Guinet, Olivier Neyrolles, Pierre Charneau, Laleh Majlessi, Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris] (IP)-TheraVectys-Université Paris Cité (UPCité), Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plate-Forme d’Histopathologie / Histopathology Platform, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Plateforme d'Innovation et de Développement de Tests Diagnostiques / Diagnostic Test Innovation and Development Core Facility, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), This work was also supported by the Programmes Transversaux de Recherche (PTR # 52-17 from Institut Pasteur to L.M. and P.C.), the EU program TBVAC2020 (contract n°643381 to P.C.), CNRS, University of Toulouse, Agence Nationale de la Recherche/Program d’Investissements d’Avenir (ANR-11-EQUIPEX-0003 to O.N.), the Fondation pour la Recherche Médicale (DEQ20160334902 to O.N.), the Bettencourt Schueller Foundation (Grants Coup d’Élan pour la Recherche Française and Explore-TB to O.N.)., European Project: 643381,H2020,H2020-PHC-2014-single-stage,TBVAC2020(2015), Hardy, David, TBVAC2020, Advancing novel and promising TB vaccine candidates from discovery to preclinical and early clinical development - TBVAC2020 - - H20202015-01-01 - 2018-12-31 - 643381 - VALID, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], Immunology, Immunology and Allergy
Abstract: International audience; Abstract Most viral vectors, including the potently immunogenic lentiviral vectors (LVs), only poorly direct antigens to the MHC-II endosomal pathway and elicit CD4 + T cells. We developed a new generation of LVs encoding antigen-bearing monomers of collectins substituted at their C-terminal domain with the CD40 ligand ectodomain to target and activate antigen-presenting cells. Host cells transduced with such optimized LVs secreted soluble collectin-antigen polymers with the potential to be endocytosed in vivo and reach the MHC-II pathway. In the murine tuberculosis model, such LVs induced efficient MHC-II antigenic presentation and triggered both CD8 + and CD4 + T cells at the systemic and mucosal levels. They also conferred a significant booster effect, consistent with the importance of CD4 + T cells for protection against Mycobacterium tuberculosis . Given the pivotal role of CD4 + T cells in orchestrating innate and adaptive immunity, this strategy could have a broad range of applications in the vaccinology field.
Published: 2022

18. Cannabis Use as a Protective Factor Against Overweight in HIV-Hepatitis C Virus Co-Infected People (ANRS CO13 HEPAVIH Cohort)

Author: Barré, Tangui, Sogni, Philippe, Zaegel-Faucher, Olivia, Wittkop, Linda, Marcellin, Fabienne, Carrieri, Patrizia, Gervais, Anne, Levier, Axel, Rosenthal, Eric, Salmon-Céron, Dominique, Protopopescu, Camelia, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des sciences de la santé publique [Marseille] (ISSPAM), Physiopathologie du système immunitaire (Inserm U1223), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Département d'hépatologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Immuno-hématologie clinique [Hôpital Sainte Marguerite - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Team MORPH3EUS (INSERM U1219 - UB - ISPED), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des maladies infectieuses et tropicales, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), Université Côte d'Azur (UCA), Service Maladies infectieuses et tropicales [AP-HP Hôpital Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and ANRS CO13 HEPAVIH Study Group
Subjects: cannabis, obesity, Health (social science), [SDV]Life Sciences [q-bio], HIV Infections, body mass index, Hepacivirus, Thinness, Humans, MESH: Hepacivirus, MESH: Overweight, MESH: Protective Factors, MESH: Hepatitis C, MESH: Humans, MESH: Thinness, Coinfection, Public Health, Environmental and Occupational Health, HIV, MESH: HIV Infections, Overweight, Protective Factors, MESH: Coinfection, chronic, Infectious Diseases, MESH: Cannabis, hepatitis C, marijuana
Abstract: International audience; Overweight is increasingly prevalent in people living with HIV (PLWH), and is a high risk factor for metabolic disorders in this population. PLWH co-infected with hepatitis C virus (HCV) have a higher risk of metabolic disorders than their mono-infected counterparts. The putative relationship between cannabis use and body weight found in the general population has never been documented in HIV-HCV co-infected people. We tested whether cannabis use is associated with body mass index (BMI), overweight, and underweight in HCV co-infected PLWH (N = 992). Mixed-effects linear and logistic regression models were used to study the association between cannabis use and the three outcomes over time. After multivariable adjustment, cannabis use was inversely associated with BMI. Cannabis use was associated with a lower and higher risk of overweight and underweight, respectively. Cannabis use should be assessed and taken into account in the clinical management of the HIV-HCV co-infected population.
Published: 2022

19. Distinct subsets of multi-lymphoid progenitors support ontogeny-related changes in human lymphopoiesis

Author: Keita, Seydou, Diop, Samuel, Lekiashvili, Shalva, Chabaane, Emna, Nelson, Elisabeth, Strullu, Marion, Arfeuille, Chloé, Guimiot, Fabien, Domet, Thomas, Duchez, Sophie, Evrard, Bertrand, Darde, Thomas, Larghero, Jerome, Verhoeyen, Els, Cumano, Ana, Macintyre, Elizabeth, Kasraian, Zeinab, Jouen, François, Goodhardt, Michele, Garrick, David, Chalmel, Frederic, Alhaj Hussen, Kutaiba, Canque, Bruno, Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Cognitions Humaine et ARTificielle (CHART), Université Paris 8 Vincennes-Saint-Denis (UP8)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Nanterre (UPN)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Hopital Saint-Louis [AP-HP] (AP-HP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), SciLicium [Rennes], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Université Paris-Saclay, Hôpital Paul Brousse, and This work was supported by the Agence de la Biomédecine, Agence National de la Recherche (ANR EpiDev), the Institut National Du Cancer (InCA B-REC), the Fondation Ramsay Générale de Santé, and by the INSERM HuDeCA network.
Subjects: adaptative immunity, [SDV]Life Sciences [q-bio], aging, early lymphoid progenitors, human lymphopoiesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, CP: Immunology, CP: Developmental biology, multi-lymphoid progenitors, development, lymphoid development architecture
Abstract: International audience; Changes in lymphocyte production patterns occurring across human ontogeny remain poorly defined. In this study, we demonstrate that human lymphopoiesis is supported by three waves of embryonic, fetal, and postnatal multi-lymphoid progenitors (MLPs) differing in CD7 and CD10 expression and their output of CD127-/+ early lymphoid progenitors (ELPs). In addition, our results reveal that, like the fetal-to-adult switch in erythropoiesis, transition to postnatal life coincides with a shift from multilineage to B lineage-biased lymphopoiesis and an increase in production of CD127+ ELPs, which persists until puberty. A further developmental transition is observed in elderly individuals whereby B cell differentiation bypasses the CD127+ compartment and branches directly from CD10+ MLPs. Functional analyses indicate that these changes are determined at the level of hematopoietic stem cells. These findings provide insights for understanding identity and function of human MLPs and the establishment and maintenance of adaptative immunity.
Published: 2023

20. Protein abundance in the midgut of wild tsetse flies ( Glossina palpalis palpalis ) naturally infected by Trypanosoma congolense s.l

Author: Tsagmo, Jean Marc, Njiokou, Flobert, Dziedziech, Alexis, Rofidal, Valerie, Hem, Sonia, Geiger, Anne, Interactions hôtes-vecteurs-parasites-environnement dans les maladies tropicales négligées dues aux trypanosomatides (UMR INTERTRYP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université de Bordeaux (UB), Université de Yaoundé I, Biologie cellulaire des Trypanosomes - Trypanosome Cell Biology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut des Sciences des Plantes de Montpellier (IPSIM), Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), Centre de Recherche sur les Filarioses et autres Maladies Tropicales - Centre for Research on Filariasis and other Tropical Diseases [Yaoundé] (CRFilMT), ARTS fellowship from the Institut de Recherche pour le Développement (IRD), and Région Languedoc-Roussillon-Appel d‧Offre «Chercheur d‧Avenir 2011
Subjects: trypanosomiasis, natural fly infection, [SDV]Life Sciences [q-bio], [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, vector competence control, tsetse fly, differential protein expression
Abstract: International audience; Tsetse flies (Glossina spp.) are major vectors of African trypanosomes, causing either Human or Animal African Trypanosomiasis (HAT or AAT). Several approaches have been developed to control the disease, among which is the anti-vector Sterile Insect Technique. Another approach to anti-vector strategies could consist of controlling the fly's vector competence through hitherto unidentified regulatory factors (genes, proteins, biological pathways, etc.). The present work aims to evaluate the protein abundance in the midgut of wild tsetse flies (Glossina palpalis palpalis) naturally infected by Trypanosoma congolense s.l. Infected and non-infected flies were sampled in two HAT/AAT foci in Southern Cameroon. After dissection, the proteomes from the guts of parasite-infected flies were compared to that of uninfected flies to identify quantitative and/or qualitative changes associated with infection. Among the proteins with increased abundance were fructose-1,6-biphosphatase, membrane trafficking proteins, death proteins (or apoptosis proteins) and SERPINs (inhibitor of serine proteases, enzymes considered as trypanosome virulence factors) that displayed the highest increased abundance. The present study, together with previous proteomic and transcriptomic studies on the secretome of trypanosomes from tsetse fly gut extracts, provides data to be explored in further investigations on, for example, mammal host immunisation or on fly vector competence modification via para-transgenic approaches.
Published: 2023

21. Qualitative monitoring of SARS-CoV-2 mRNA vaccination in humans using droplet microfluidics

Author: Broketa, Matteo, Sokal, Aurélien, Mor, Michael, Canales-Herrerias, Pablo, Perima, Angga, Meola, Annalisa, Fernández, Ignacio, Iannascoli, Bruno, Chenon, Guilhem, Vandenberghe, Alexis, Languille, Laetitia, Michel, Marc, Godeau, Bertrand, Gallien, Sebastien, Melica, Giovanna, Backovic, Marija, Rey, Felix, Baudry, Jean, Freund, Natalia, Mahevas, Matthieu, Bruhns, Pierre, Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Diaccurate SAS, Physiologie, physiopathologie et thérapeutique (ED 394), Sorbonne Université (SU), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Tel Aviv University (TAU), Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire Colloïdes et Matériaux Divisés (LCMD), Chimie-Biologie-Innovation (UMR 8231) (CBI), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), M.B. is the recipient of a CIFRE PhD fellowship. P.C-H. was supported by a fellowship from the French Fondation pour la Recherche Médicale (FRM). A.S. was supported by a Poste d’Accueil from INSERM, I.F. by a fellowship from the French Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS). P.B. acknowledges funding from the Agence Nationale de la Recherche (ANR) ANR-18-CE15-0001 project Autoimmuni-B and ANR-14-CE16-0011 project DROPmAbs, from the Institut Carnot Pasteur Microbes et Santé, from the CAPNET (Comité ad-hoc de pilotage national des essais thérapeutiques et autres recherches, French government) MEMO-VOC, from the Institut Pasteur and from the Institut National de la Santé et de la Recherche Médicale (INSERM). M.Ma. acknowledges funding from the Agence Nationale de la Recherche and the Fondation pour la Recherche Médicale (ANR, MEMO-COV-2 -FRM). Assistance Publique – Hôpitaux de Paris (AP-HP, Département de la Recherche Clinique et du Développement) was the promotor and the sponsor of MEMO-COV-2. J.B. acknowledges funding from the French government through BPIFrance under the frame Programme d’Investissements d’Avenir (CELLIGO Project), the Institut Pierre-Gilles de Gennes through the laboratoire d’excellence, Investissements d’avenir programs ANR-10-IDEX-0001-02 PSL, ANR-10- EQPX-34 and ANR-10-LABX-3. N.T.F. acknowledges funding from the Israeli Science Foundation grants #1422/18 and #3711/20 and Marguerite Stolz Research Fellowship. Work in the Unit of Structural Virology was funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur., ANR-18-CE15-0001,Autoimmuni-B,Etude de la rupture de tolérance dans une maladie humaine autoimmune médiée par les lymphocytes B(2018), ANR-14-CE16-0011,DROP-mAbs,Analyse en profondeur de répertoires d'anticorps par microfluidique en gouttelettes couplé à du séquençage haut-débit pour le diagnostic et la découverte d'anticorps thérapeutiques(2014), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-10-EQPX-0034,IPGG,Institut Pierre Gilles de Gennes pour la microfluidique(2010), and ANR-10-LABX-0003,BCDiv,Biological and Cultural Diversities : Origins, Evolution, Interactions, Future(2010)
Subjects: [SDV]Life Sciences [q-bio], [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology
Abstract: International audience; SARS-CoV-2 mRNA vaccination generates protective B cell responses targeting the SARS-CoV-2 spike glycoprotein. Whereas anti-spike memory B cell responses are long-lasting, the anti-spike humoral antibody response progressively wanes, making booster vaccinations necessary for maintaining protective immunity. Here we investigated qualitatively the plasmablast responses by measuring from single cells within hours of sampling the affinity of their secreted antibody for the SARS-CoV-2 spike receptor binding domain in cohorts of BNT162b2-vaccinated naive and COVID-19-recovered individuals. Using a unique droplet microfluidic and imaging approach, we analyzed >4,000 single IgG-secreting cells revealing high inter-individual variability in affinity for RBD with variations over 4 logs. High-affinity plasmablasts were induced by BNT162b2 vaccination against Hu-1 and Omicron RBD but disappeared quickly thereafter, whereas low-affinity plasmablasts represented >65% of the plasmablast response at all timepoints. Our droplet-based method thus proves efficient at fast and qualitative immune monitoring and should be helpful for optimization of vaccination protocols.
Published: 2023

22. Modified Plasmodium falciparum Ring-Stage Survival Assay with ML10 Kinase Inhibitor

Author: Lucien Platon, David A. Baker, Didier Ménard, Génétique du paludisme et résistance - Malaria Genetics and Resistance, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Sorbonne Université (SU), Biologie de Plasmodium et Vaccins - Malaria Parasite Biology and Vaccines, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), London School of Hygiene and Tropical Medicine (LSHTM), Dynamique des interactions hôte pathogène (DIHP), Université de Strasbourg (UNISTRA), and CHU Strasbourg
Subjects: Pharmacology, Infectious Diseases, ring-stage survival assay, [SDV]Life Sciences [q-bio], Plasmodium falciparum, malaria, Pharmacology (medical), artemisinin resistance
Abstract: International audience; The ring-stage survival assay is the reference assay to measure in vitro Plasmodium falciparum artemisinin partial resistance. The main challenge of the standard protocol is to generate 0-to-3-h postinvasion ring stages (the stage least susceptible to artemisinin) from schizonts obtained by sorbitol treatment and Percoll gradient. We report here a modified protocol facilitating the production of synchronized schizonts when multiple strains are tested simultaneously, by using ML10, a protein kinase inhibitor, that reversibly blocks merozoite egress.
Published: 2023

23. Deafness: from genetic architecture to gene therapy

Author: Christine Petit, Crystel Bonnet, Saaïd Safieddine, Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Collège de France (CdF (institution)), Centre National de la Recherche Scientifique (CNRS), This work was supported by Fondation pour l’Audition (FPA IDA05 to CP, FPA IDA08 to SS), Ile de France (DIM Thérapie génique to C.P. and S.S.), EARGENCURE (ANR-17-CE18–0027 to S.S.), PRESAGE (ANR-21-CE14–0075 to C.P.), RHU AUDINNOVE (ANR-18-RHUS-0007 to C.P. and S.S.)., ANR-21-CE14-0075,PRESAGE,Vers une audiologie de précision pour la presbyacousie(2021), ANR-17-CE18-0027,EARGENCURE,Restauration, par thérapie génique, de l'audition et de l'équilibre chez des souris modèles de surdités et troubles vestibulaires humains(2017), and ANR-18-RHUS-0007,AUDINNOVE,Treating congenital hearing impairment(2018)
Subjects: [SDV]Life Sciences [q-bio], Genetics, Molecular Biology, Genetics (clinical)
Abstract: International audience; Progress in deciphering the genetic architecture of human sensorineural hearing impairment (SNHI) or loss, and multidisciplinary studies of mouse models, have led to the elucidation of the molecular mechanisms underlying auditory system function, primarily in the cochlea, the mammalian hearing organ. These studies have provided unparalleled insights into the pathophysiological processes involved in SNHI, paving the way for the development of inner-ear gene therapy based on gene replacement, gene augmentation or gene editing. The application of these approaches in preclinical studies over the past decade has highlighted key translational opportunities and challenges for achieving effective, safe and sustained inner-ear gene therapy to prevent or cure monogenic forms of SNHI and associated balance disorders.
Published: 2023

24. Nutrient-dependent regulation of β-cell proinsulin content

Author: Xiaoxi Xu, Anoop Arunagiri, Maroof Alam, Leena Haataja, Charles R. Evans, Ivy Zhao, Roberto Castro-Gutierrez, Holger A. Russ, Caroline Demangel, Ling Qi, Billy Tsai, Ming Liu, Peter Arvan, University of Michigan [Ann Arbor], University of Michigan System, Tianjin Medical University, University of Florida [Gainesville] (UF), Immunobiologie et Thérapie - Immunobiology and Therapy, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Michigan [Dearborn], This work was supported primarily by NIH R01 DK111174 (to LQ, BT, and PA) and DK48280 (to PA). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding was also from the National Natural Science Foundation of China (82000796), the PUMC Youth Fund supported by the Fundamental Research Funds for the Central Universities (3332020080), the Tianjin Municipal Science and Technology Commission (18JCQNJC82100), and the China Scholarship Council (201806940006) to XX, as well as the National Natural Science Foundation of China 81620108004 and 81830025, and the National Key R&D Program 2019YFA0802502 to M.L. The H.R. lab has been supported by NIH/NIDDK grants NIDDK RRID:SCR014393, and UC24 DK104162, R01DK12044, R01DK132387, and the JDRF. C.D. acknowledges core support from Institut Pasteur and INSERM (U1224).
Subjects: amino acids, endoplasmic reticulum, preproinsulin, [SDV]Life Sciences [q-bio], [SDV.IMM]Life Sciences [q-bio]/Immunology, Cell Biology, phospho-eIF2α, biosynthesis, Molecular Biology, Biochemistry
Abstract: International audience; Insulin is made from proinsulin, but the extent to which fasting/feeding controls the homeostatically-regulated proinsulin pool in pancreatic β-cells remains largely unknown. Here, we first examined β-cell lines (INS1E and Min6, which proliferate slowly and are routinely fed fresh medium every 2-3 days) and found that the proinsulin pool size responds to each feeding within 1-2 hours; affected both by the quantity of fresh nutrients and the frequency with which they are provided. We observed no effect of nutrient feeding on the overall rate of proinsulin turnover as quantified from cycloheximide-chase experiments. We show that nutrient feeding is primarily linked to rapid de-phosphorylation of translation initiation factor eIF2α, presaging increased proinsulin levels (and thereafter, insulin levels), followed by its re-phosphorylation during the ensuing hours that correspond to a fall in proinsulin levels. The decline of proinsulin levels is blunted by the integrated stress response inhibitor, ISRIB, or by inhibition of eIF2α re-phosphorylation with a GCN2 (not PERK) kinase inhibitor. In addition, we demonstrate that amino acids contribute importantly to the proinsulin pool; mass spectrometry shows that β-cells avidly consume extracellular glutamine, serine, and cysteine. Finally, we show that in both rodent and human pancreatic islets, fresh nutrient availability dynamically increases preproinsulin, which can be quantified without pulse-labeling. Thus, the proinsulin available for insulin biosynthesis is rhythmically controlled by fasting/feeding cycles.
Published: 2023

25. Tumor-intrinsic sensitivity to the pro-apoptotic effects of IFN-γ is a major determinant of CD4+ CAR T-cell antitumor activity

Author: Morgane Boulch, Marine Cazaux, Alexis Cuffel, Marion V. Guerin, Zacarias Garcia, Ruby Alonso, Fabrice Lemaître, Alexander Beer, Béatrice Corre, Laurie Menger, Capucine L. Grandjean, Florence Morin, Catherine Thieblemont, Sophie Caillat-Zucman, Philippe Bousso, Dynamiques des Réponses immunes - Dynamics of Immune Responses, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Institut Gustave Roussy (IGR), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), The work was supported by Institut Pasteur, INSERM, INCa (PLBIO21-104) and an Advanced grant (ENLIGHTEN) from the European Research Council (P.B.)., We thank members of the Bousso laboratory for critical review of the paper. We are grateful to F. Sepulveda for providing Prf1−/− mice. We acknowledge the mouse facility and CB UTechS at Institut Pasteur for support in conducting the present study, European Project: 741167,ERC-2016-ADG,ENLIGHTEN(2018), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), and Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay
Subjects: Cancer Research, Oncology, [SDV]Life Sciences [q-bio]
Abstract: CD4+ T cells and CD4+ chimeric antigen receptor (CAR) T cells display highly variable antitumor activity in preclinical models and in patients; however, the mechanisms dictating how and when CD4+ T cells promote tumor regression are incompletely understood. With the help of functional intravital imaging, we report that interferon (IFN)-γ production but not perforin-mediated cytotoxicity was the dominant mechanism for tumor elimination by anti-CD19 CD4+ CAR T cells. Mechanistically, mouse or human CD4+ CAR T-cell-derived IFN-γ diffused extensively to act on tumor cells at distance selectively killing tumors sensitive to cytokine-induced apoptosis, including antigen-negative variants. In anti-CD19 CAR T-cell-treated patients exhibiting elevated CAR CD4:CD8 ratios, strong induction of serum IFN-γ was associated with increased survival. We propose that the sensitivity of tumor cells to the pro-apoptotic activity of IFN-γ is a major determinant of CD4+ CAR T-cell efficacy and may be considered to guide the use of CD4+ T cells during immunotherapy.
Published: 2023

26. Differential transmissibility to Anopheles arabiensis of Plasmodium vivax gametocytes in patients with diverse Duffy blood group genotypes

Author: Abate, Andargie, Hassen, Jifar, Dembele, Laurent, Menard, Didier, Golassa, Lemu, Addis Ababa University (AAU), Bahir Dar University (BDU), Adama Science and Technology University, Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Génétique du paludisme et résistance - Malaria Genetics and Resistance, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Dynamique des interactions hôte pathogène (DIHP), Université de Strasbourg (UNISTRA), CHU Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), and This project is part of the European and Developing Countries Clinical Trials Partnership (EDCTP2) program supported by the European Union (grant number TMA2017CDF-1892-HypnoBio).
Subjects: Duffy blood group, Infectious Diseases, Anopheles mosquitoes, [SDE]Environmental Sciences, Parasitology, Ethiopia, Plasmodium vivax, Membrane feeding assay
Abstract: Background Measuring risk of malaria transmission is complex, especially in case of Plasmodium vivax. This may be overcome using membrane feeding assays in the field where P. vivax is endemic. However, mosquito-feeding assays are affected by a number of human, parasite and mosquito factors. Here, this study identified the contributions of Duffy blood group status of P. vivax-infected patients as a risk of parasite transmission to mosquitoes. Methods A membrane feeding assay was conducted on a total of 44 conveniently recruited P. vivax infected patients in Adama city and its surroundings in East Shewa Zone, Oromia region, Ethiopia from October, 2019 to January, 2021. The assay was performed in Adama City administration. Mosquito infection rates were determined by midgut dissections at seven to 8 days post-infection. Duffy genotyping was defined for each of the 44 P. vivax infected patients. Results The infection rate of Anopheles mosquitoes was 32.6% (296/907) with 77.3% proportion of infectious participants (34/44). Infectiousness of participants to Anopheles mosquitoes appeared to be higher among individuals with homozygous Duffy positive blood group (TCT/TCT) than heterozygous (TCT/CCT), but the difference was not statistically significant. The mean oocyst density was significantly higher among mosquitoes fed on blood of participants with FY*B/FY*BES than other genotypes (P = 0.001). Conclusion Duffy antigen polymorphisms appears to contribute to transmissibility difference of P. vivax gametocytes to Anopheles mosquitoes, but further studies are required.
Published: 2023

27. Immunomodulation under the lens of real‐time in vivo imaging

Author: Bousso, Philippe, Grandjean, Capucine, Dynamiques des Réponses immunes - Dynamics of Immune Responses, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), The work was supported by Institut Pasteur, Inserm, La Ligue contre le Cancer (P.B.), ANR JCJC (C.L.G) and an Advanced grant (ENLIGHTEN) from the European Research Council (P.B.)., and European Project: 741167,ERC-2016-ADG,ENLIGHTEN(2018)
Subjects: multiphoton microscopy, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunology and Allergy, intravital imaging, fluorescent reporters, immunotherapies, immunomodulation
Abstract: International audience; Modulation of cells and molecules of the immune system not only represents a major opportunity to treat a variety of diseases including infections, cancer, autoimmune and inflammatory disorders but could also help understand the intricacies of immune responses. A detailed mechanistic understanding of how a specific immune intervention may provide clinical benefit is essential for the rational design of efficient immunomodulators. Visualizing the impact of immunomodulation in real-time and in vivo has emerged as an important approach to achieve this goal. In this review, we aim to illustrate how multiphoton intravital imaging has helped clarify the mode of action of immunomodulatory strategies such as antibodies or cell therapies. We also discuss how optogenetics combined with imaging will further help manipulate and precisely understand immunomodulatory pathways. Combined with other single-cell technologies, in vivo dynamic imaging has therefore a major potential for guiding preclinical development of immunomodulatory drugs.
Published: 2023

28. Mice Humanized for MHC and hACE2 with High Permissiveness to SARS-CoV-2 Omicron Replication

Author: Fabien Le Chevalier, Pierre Authié, Sébastien Chardenoux, Maryline Bourgine, Benjamin Vesin, Delphine Cussigh, Yohann Sassier, Ingrid Fert, Amandine Noirat, Kirill Nemirov, François Anna, Marion Bérard, Françoise Guinet, David Hardy, Pierre Charneau, François Lemonnier, Francina Langa-Vives, Laleh Majlessi, Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris] (IP)-TheraVectys-Université Paris Cité (UPCité), Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Animalerie Centrale (plateforme) - Central Animal Facility (platform) (C2RA), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Plate-Forme d’Histopathologie / Histopathology Platform, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur et Theravectys
Subjects: HLA, Infectious Diseases, SARS-CoV-2, [SDV]Life Sciences [q-bio], Immunology, Transgenesis, Omicron variant, Microbiology, COVID-19 animal model
Abstract: International audience; Human Angiotensin-Converting Enzyme 2 (hACE2) is the major receptor enabling host cell invasion by SARS-CoV-2 via interaction with Spike. The murine ACE2 does not interact efficiently with SARS CoV-2 Spike and therefore the laboratory mouse strains are not permissive to SARS-CoV-2 replication. Here, we generated new hACE2 transgenic mice, which harbor the hACE2 gene under the human keratin 18 promoter, in “HHD-DR1” background. HHD-DR1 mice are fully devoid of murine Major Histocompatibility Complex (MHC) molecules of class-I and -II and express only MHC molecules from Human Leukocyte Antigen (HLA) HLA 02.01, DRA01.01, DRB1.01.01 alleles, widely expressed in human populations. We selected three transgenic strains, with various hACE2 mRNA expression levels and distinctive profiles of lung and/or brain permissiveness to SARS-CoV-2 replication. These new hACE2 transgenic strains display high permissiveness to the replication of SARS-CoV-2 Omicron sub-variants, while the previously available B6.K18-ACE22Prlmn/JAX mice have been reported to be poorly susceptible to infection with Omicron. As a first application, one of these MHC- and ACE2-humanized strains was successfully used to show the efficacy of a lentiviral-based COVID-19 vaccine
Published: 2023

29. Bacterial capsular polysaccharides with antibiofilm activity share common biophysical and electrokinetic properties

Author: Joaquín Bernal-Bayard, Jérôme Thiebaud, Marina Brossaud, Audrey Beaussart, Céline Caillet, Yves Waldvogel, Laetitia Travier, Sylvie Létoffé, Thierry Fontaine, Bachra Rokbi, Philippe Talaga, Christophe Beloin, Noëlle Mistretta, Jérôme F. L. Duval, Jean-Marc Ghigo, Génétique des Biofilms - Genetics of Biofilms, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidad de Sevilla / University of Sevilla, Sanofi Pasteur [Marcy-l'Étoile, France], Laboratoire Interdisciplinaire des Environnements Continentaux (LIEC), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Terre et Environnement de Lorraine (OTELo), Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Interactions cerveau-immunité - Brain-immune communication, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Biologie et Pathogénicité fongiques - Fungal Biology and Pathogenicity (BPF), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 842629,Salmofish, Duval, Jerome, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, and Tracing T3SS effectors in vivo during Salmonella infection in the zebrafish model - Salmofish - 0000-00-00 - 0000-00-00 - 842629 - VALID
Subjects: [SDV] Life Sciences [q-bio], Multidisciplinary, [SDV]Life Sciences [q-bio], [CHIM] Chemical Sciences, General Physics and Astronomy, [CHIM]Chemical Sciences, General Chemistry, General Biochemistry, Genetics and Molecular Biology
Abstract: Bacterial biofilms are surface-attached communities that are difficult to eradicate due to a high tolerance to antimicrobial agents. The use of non-biocidal surface-active compounds to prevent the initial adhesion and aggregation of bacterial pathogens is a promising alternative to antibiotic treatments and several antibiofilm compounds have been identified, including some capsular polysaccharides released by various bacteria. However, the lack of chemical and mechanistic understanding of the activity of these high-molecular-weight polymers limits their use for control of biofilm formation. Here, we screened a collection of 32 purified capsular polysaccharides and identified seven new compounds with non-biocidal activity against biofilms formed by Escherichia coli and/or Staphylococcus aureus. We analyzed the polysaccharide mobility under applied electric field conditions and showed that active and inactive polysaccharide polymers display distinct electrokinetic properties and that all active macromolecules shared high intrinsic viscosity features. Based on these characteristics, we identified two additional antibiofilm capsular polysaccharides with high density of electrostatic charges and their permeability to fluid flow. Our study therefore provides insights into key biophysical properties discriminating active from inactive polysaccharides. This characterization of a specific electrokinetic signature for polysaccharides displaying antibiofilm activity opens new perspectives to identify or engineer non-biocidal surface-active macromolecules to control biofilm formation in medical and industrial settings.Significance statementSome bacteria produce non-biocidal capsular polysaccharides that reduce the adhesion of bacterial pathogens to surfaces. Due to a lack of molecular and structural definition, the basis of their antiadhesion activity is unknown, thus hindering their prophylactic use for biofilm control. Here, we identified nine new active compounds and compared their composition, structure and biophysical properties with other inactive capsular polysaccharides. Despite the absence of specific molecular motif, we demonstrate that all active polysaccharides share common electrokinetic properties that distinguish them from inactive polymers. This characterization of the biophysical properties of antibiofilm bacterial polysaccharide provides key insights to engineer non-biocidal and bio-inspired surface-active compounds to control bacterial adhesion in medical and industrial settings.
Published: 2023

30. Stromal regulation of the intestinal barrier

Author: Sylvestre, Marvin, Di Carlo, Selene, Peduto, Lucie, Stroma, inflammation et réparation tissulaire - Stroma, Inflammation and Tissue Repair, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), The lab has received funding from the European Research Council (ERC) Consolidator grant 648428-PERIF (to LP), INSERM, and Institut Pasteur., and European Project: 648428,H2020,ERC-2014-CoG,PERIF(2015)
Subjects: [SDV]Life Sciences [q-bio], Immunology, Immunology and Allergy
Abstract: International audience; The intestinal barrier is a complex structure that allows the absorption of nutrients while ensuring protection against intestinal pathogens and balanced immunity. The development and maintenance of a functional intestinal barrier is a multifactorial process that is only partially understood. Here we review novel findings on the emerging role of mesenchymal cells in this process using insights gained from lineage tracing approaches, Cre-based gene deletion, and single-cell transcriptomics. The current evidence points toward a key organizer role for distinct mesenchymal lineages in intestinal development and homeostasis, regulating both epithelial and immune components of the intestinal barrier. We further discuss recent findings on functional mesenchymal heterogeneity and implications for intestinal regeneration and inflammatory intestinal pathologies.
Published: 2023

31. The neuropeptide VIP potentiates intestinal innate type 2 and type 3 immunity in response to feeding

Author: Maud Pascal, Alexander Kazakov, Grégoire Chevalier, Lola Dubrule, Julie Deyrat, Alice Dupin, Soham Saha, Ferdinand Jagot, Kurt Sailor, Sophie Dulauroy, Carine Moigneu, Yasmine Belkaid, Gabriel Lepousez, Pierre-Marie Lledo, Christoph Wilhelm, Gérard Eberl, Perception et Mémoire / Perception and Memory, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Microenvironnement et Immunité - Microenvironment and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Ecole doctorale Cerveau Cognition et Comportement [Paris] (ED 158 - 3C), Sorbonne Université (SU), Universität Bonn = University of Bonn, National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), This work was supported by Institut Pasteur, a seed grant from the Institut Pasteur Strategic Research Axis 3, INSERM, CNRS, the life insurance company 'AG2R-La-Mondiale' and grant ANR-16-CE15-0021-01 from the Agence Nationale de la Recherche Scientifique. C.W. and A.K. were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC2151 – 390873048 and program grants from the DFG (SPP1937, WI 4554/1-1 and WI 4554/1-2)., We thank all members of the Microenvironment and Immunity unit, the Perception and Memory unit, and the Stroma, Inflammation and Tissue Repair unit, in particular Bernadette Polomack for mouse genotyping. We also thank Uwe Maskos, Fani Koukouli and David Digregorio for providing us VIPCre Mice, and Meinrad Busslinger for the Gata3GFP mice. We thank Pierre Bost for sharing its expertise on image analysis, Jacques Serizay for providing guidance in data visualization for Fig. 1, Christelle Ganneau and Sylvie Bay for sharing their expertise on peptides biochemistry as well as Martine Jacob and Catherine Fayolle for their precious technical support with mice. M.P. is a recipient of a fellowship from the French Ministère de l’Education Nationale et de la Recherche., and ANR-16-CE15-0021,PG-Brain,Modulation de l'activité du cerveau par le peptidoglycan bactérien(2016)
Subjects: Intestines, Neuropeptides, Immunology, Cytokines, Immunology and Allergy, Lymphocytes, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Immunity, Innate, Vasoactive Intestinal Peptide
Abstract: International audience; The nervous system and the immune system both rely on an extensive set of modalities to perceive and act on perturbations in the internal and external environments. During feeding, the intestine is exposed to nutrients that may contain noxious substances and pathogens. Here we show that Vasoactive Intestinal Peptide (VIP), produced by the nervous system in response to feeding, potentiates the production of effector cytokines by intestinal type 2 and type 3 innate lymphoid cells (ILC2s and ILC3s). Exposure to VIP alone leads to modest activation of ILCs, but strongly potentiates ILCs to concomitant or subsequent activation by the inducer cytokines IL-33 or IL-23, via mobilization of cAMP and energy by glycolysis. Consequently, VIP increases resistance to intestinal infection by the helminth Trichuris muris and the enterobacteria Citrobacter rodentium. These findings uncover a functional neuro-immune crosstalk unfolding during feeding that increases the reactivity of innate immunity necessary to face potential threats associated with food intake
Published: 2022

32. Étude de la résistance de Plasmodium falciparum et des phénotypes de dormance induite par l'artémisinine : du patient à la cellule

Author: Platon, Lucien, Génétique du paludisme et résistance - Malaria Genetics and Resistance, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Ecole Doctorale Complexité du Vivant (ED515), Sorbonne Université (SU), Sorbonne Université, and Didier Ménard
Subjects: Paludisme, Dormance, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Resistance, Dormancy, Artemisinin, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Résistance, Malaria, Artémisinine
Abstract: Plasmodium falciparum is the causative agent of the most severe form of malaria. In 2022, the disease was responsible for 619,000 deaths and 247 million cases worldwide. P. falciparum has a complex life cycle in the mosquito vector and in the human host. Artemisinin and its derivatives are used in combination with partner drugs. Artemisinin-based combination therapies (ACT) are currently the most effective treatment available. Unfortunately, malaria control efforts are threatened by mutations in the Pfkelch13 gene of P. falciparum, which confer partial resistance to artemisinin. This resistance to artemisinin is also associated with a drug-induced dormancy phenotype, which allows a proportion of parasites to survive exposure to the drug. This thesis focuses on artemisinin resistance and drug-induced dormancy through a multidisciplinary approach. It combines public health, technical optimisation and basic research. As part of the public health work, we have detected the emergence of a new double mutant Pfkelch13-R622I resistant to artemisinin in patients in Eritrea. This mutant is associated with deletions in the Pfhrp2 and Pfhrp3 genes, reducing the performances of HRP2-based rapid diagnostic tests. These data highlight the urgency of developing new control strategies in the context of the emergence of artemisinin resistance across the African continent. An optimised version of the Ring-Stage Survival Assay, the main diagnostic tool used to detect artemisininresistant P. falciparum parasites, was developed. This optimisation allows for the simultaneous synchronisation of several P. falciparum strains with different genetic backgrounds, thus enabling multiple RSA tests to be performed in parallel in a reliable and reproducible manner. Finally, basic research focused on studying drug-induced dormancy as a mechanism of artemisinin resistance. We were able to demonstrate important changes in the metabolism of dormant ring stage parasites based on amino acid catabolism. We have also shown that dormancy can be induced by extracellular stress signals released by dying mature stage parasites. Finally, our data indicate that the synchronous early ring stage of a clonal parasite population exhibits high transcriptional diversity. All the data presented suggest that dormancy is a constitutive mechanism at P. falciparum ring stage, mediated by extracellular signals of an unknown nature and concentration, independent of Pfkelch13 genotypes. We are convinced this work may provide a basis for developing a new therapeutic strategy based on interfering with the parasite's extracellular communications.; Plasmodium falciparum est l'agent pathogène responsable des formes les plus graves de paludisme. P. falciparum a été responsable de 619 0000 décès et 247 millions de cas de paludisme dans le monde en 2022. Le parasite possède un cycle de vie complexe qui se déroule chez les moustiques du genre Anophèles et les hôtes humains. L'artémisinine et ses dérivés, associés à des médicaments partenaires, constituent les thérapies combinées à base d'artémisinine (TCA) et sont les traitements les plus efficaces actuellement disponibles. Malheureusement, depuis plus de 15 ans, des souches de P. falciparum originaire d’Asie du Sud-est présentent une résistance partielle à l'artémisinine et menacent les efforts de lutte contre le paludisme. Cette résistance partielle a pu être associée à la présence de mutations au sein du gène Pfkelch13 mais également à un retard de croissance (dormance) induit par l’artémisinine, permettant à une partie des parasites de survivre à la drogue. Cette thèse a pour objectif de mieux comprendre les mécanismes sous-jacents à la résistance à l'artémisinine. Elle s'articule autour de 3 axes incluant la compréhension de l’épidémiologie de la résistance en Afrique, l’amélioration des outils permettant de détecter la résistance et l’étude des mécanismes moléculaires et cellulaires. La première partie décrit l'émergence en Érythrée d'un double mutant Pfkelch13 résistant à l'artémisinine grâce à la mutation R622I mais indétectable par les tests de diagnostic rapide car dépourvu des gènes Pfhrp2 et Pfhrp3. Ces données s'inscrivent dans un récent contexte d'émergence de la résistance de P. falciparum à l'artémisinine à travers le continent africain et soulignent l'urgence de mettre en place de nouvelles stratégies de contrôle. Dans la seconde partie de ce travail, une version optimisée du Ring-Stage Survival Assay, un outil de diagnostic clé pour détecter les souches de P. falciparum résistantes à l'artémisinine, a été développée. Cette optimisation du test permet la synchronisation simultanée de plusieurs souches de P. falciparum avec des profils de croissance in vitro différents, permettant de réaliser en parallèle de manière fiable et reproductible, des tests RSA sur plusieurs souches. La troisième partie s'est concentrée sur l'étude de la dormance induite par l'artémisinine en tant que mécanisme de résistance. Nous avons pu mettre en évidence des changements importants dans le métabolisme des stades rings dormants, basés sur le catabolisme des acides aminés. De plus, nous avons pu faire la lumière sur l'inductibilité de la dormance, chez les parasites au stade ring, par des signaux de stress extracellulaires libérés lors de la mort de parasites matures. Enfin, des données préliminaires d’analyse transcriptomique à l’échelle de l’individu a révélé l’existence d’une étonnante diversité parmi les stades rings synchrones et issus d'une souche clonale. Finalement, l'ensemble des données présentées ici suggèrent que la dormance est un mécanisme constitutif chez le stade ring de P. falciparum, dépendant de l'exposition à des signaux extracellulaire de nature et concentration inconnue, indépendant du génotype Pfkelch13. Nous sommes convaincus que ces travaux peuvent servir de base au développement de nouvelle stratégie thérapeutique, basée sur la perturbation des communications extracellulaires du parasite, l'inhibition de l'entrée en dormance et le maintien du parasite dans un état de susceptibilité à l'artémisinine.
Published: 2023

33. Defensive‐lipid droplets: Cellular organelles designed for antimicrobial immunity

Author: Rémi Safi, Miguel Sánchez‐Álvarez, Marta Bosch, Caroline Demangel, Robert G. Parton, Albert Pol, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Josep Carreras Leukaemia Research Institute (IJC), Centro Nacional de Investigaciones Cardiovasculares Carlos III [Madrid, Spain] (CNIC), Instituto de Salud Carlos III [Madrid] (ISC), Instituto de Investigaciones Biomédicas Alberto Sols [Madrid, Spain] (IIBM), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Immunobiologie et Thérapie - Immunobiology and Therapy, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institute for Molecular Bioscience, University of Queensland [Brisbane], Institució Catalana de Recerca i Estudis Avançats (ICREA), and RS is recipient of the Lady Tata Memorial Trust grant for leukemia research and the Marie Skłodowska-Curie Actions Postdoctoral Fellowship (MSCA-PF) granted by the European commission. MS-A is recipient of a Ramón y Cajal researcher contract and a research grant from the Spanish Ministerio de Innovación y Ciencia (RYC2020-029690 and PID2021-128106NA-I00). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MCIN and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033). AP and MB are supported by I+D+i RETOS INVESTIGACIÓN from the Ministerio de Ciencia e Investigación (MICINN, PID2021-127043OB-I00) and the CERCA Programme/Generalitat de Catalunya. AP is supported by the H2020-MSCA-ITN-2018, 953489 (ENDOCONNECT). RGP is a Laureate Fellow of the Australian Research Council. AP, RGP, and CD are supported by the ERC Synergy Grant ERC-2022-SYG, 101071784 (DRIMMS).
Subjects: lipid droplets, [SDV]Life Sciences [q-bio], Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunology and Allergy, interferon, virus, parasites, bacteria, innate immunity
Abstract: International audience; Microbes have developed many strategies to subvert host organisms, which, in turn, evolved several innate immune responses. As major lipid storage organelles of eukaryotes, lipid droplets (LDs) are an attractive source of nutrients for invaders. Intracellular viruses, bacteria, and protozoan parasites induce and physically interact with LDs, and the current view is that they "hijack" LDs to draw on substrates for host colonization. This dogma has been challenged by the recent demonstration that LDs are endowed with a protein-mediated antibiotic activity, which is upregulated in response to danger signals and sepsis. Dependence on host nutrients could be a generic "Achilles' heel" of intracellular pathogens and LDs a suitable chokepoint harnessed by innate immunity to organize a front-line defense. Here, we will provide a brief overview of the state of the conflict and discuss potential mechanisms driving the formation of the 'defensive-LDs' functioning as hubs of innate immunity.
Published: 2023

34. Pholcodine exposure increases the risk of perioperative anaphylaxis to neuromuscular blocking agents: the ALPHO case-control study

Author: Paul Michel Mertes, Nadine Petitpain, Charles Tacquard, Marion Delpuech, Cédric Baumann, Jean Marc Malinovsky, Dan Longrois, Aurélie Gouel-Cheron, Diane Le Quang, Pascal Demoly, Jean Louis Guéant, Pierre Gillet, Emmanuelle Aguinet, Pol André Apoil, Jean Eric Autegarden, Faiza Bettayeb, Céline Biermann, Maryline Bordes-demolis, Anca Chiriac, Pierre Antoine Darene, Frédéric Deblay, Sabrina Dessard, Charles Dzviga, Hassan El Hanache, Alain Facon, Yannick Fuhrer, Noémie Gest, Marion Gouitaa, Adela Harpan, Cyrille Hoarau, Lisa Le Guillou, Laurence Lepeltier, Claire Mailhol, Delphine Mariotte, Yannick Meunier, Isabelle Migueres, Martine Morisset, Catherine Neukirch, Dalila Nouar, Yann Ollivier, Isabelle Orsel, Omar Outtas, Minaxi Patel, Christelle Pellerin, Isabelle Petit, Anaïs Pipet, Cécile Rochefort-Morel, Claire Schwartz, Sandrine Seltzer, Alice Seringulian, Angèle Soria, Lilia Soufir, Rodolphe Stenger, Céline Tummino, Marion Verdaguer, Les Hôpitaux Universitaires de Strasbourg (HUS), Biologie et Pharmacologie des Plaquettes sanguines : hémostase, thrombose, transfusion (BPP), Université de Strasbourg (UNISTRA)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Nouvel Hôpital Civil de Strasbourg, Centre Régional de PharmacoVigilance de Lorraine (CRPV Lorraine), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Département Méthodologie Promotion Investigation [CHRU Nancy] (MPI), Centre Hospitalier Universitaire de Reims (CHU Reims), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), Service d'anesthésie - réanimation chirurgicale [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre de référence des maladies héréditaires du métabolisme (MaMEA Nancy-Brabois), Service d'Hépato-gastro-entérologie [CHRU Nancy], Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Service de Pharmacologie Clinique et Toxicologie [CHRU Nancy], The ALPHO study NCT02250729 was requested and supported by the European Medicines Agency (EMA). It was funded by a consortium of pharmaceutical companies marketing pholcodine (Zambon, Urgo, Les Laboratoires Pierre Fabre, Boots, Hepatoum, Biocodex, Sanofi, Laboratoires Bouchara Recordati, GlaxoSmithKline, Alliance Pharmaceuticals Ltd, Bells Healthcare, Pinewood, T & R, Ernest Jackson, Vemedia)., and ALPHO Study Group: Emmanuelle Aguinet, Pol André Apoil, Jean Eric Autegarden, Faiza Bettayeb, Céline Biermann, Maryline Bordes-Demolis, Anca Chiriac, Pierre Antoine Darene, Frédéric Deblay, Sabrina Dessard, Charles Dzviga, Hassan El Hanache, Alain Facon, Yannick Fuhrer, Noémie Gest, Marion Gouitaa, Adela Harpan, Cyrille Hoarau, Lisa Le Guillou, Laurence Lepeltier, Claire Mailhol, Delphine Mariotte, Yannick Meunier, Isabelle Migueres, Martine Morisset, Catherine Neukirch, Dalila Nouar, Yann Ollivier, Isabelle Orsel, Omar Outtas, Minaxi Patel, Christelle Pellerin, Isabelle Petit, Anaïs Pipet, Cécile Rochefort-Morel, Claire Schwartz, Sandrine Seltzer, Alice Seringulian, Angèle Soria, Lilia Soufir, Rodolphe Stenger, Céline Tummino, Marion Verdaguer
Subjects: Anesthesiology and Pain Medicine, [SDV]Life Sciences [q-bio], anaphylaxis, anaesthesia, quaternary ammonium compounds, neuromuscular blocking agents, pholcodine
Abstract: International audience; BackgroundNeuromuscular blocking agents (NMBAs) are among the leading cause of perioperative anaphylaxis, and most of these reactions are IgE mediated. Allergic sensitisation induced by environmental exposure to other quaternary ammonium-containing compounds, such as pholcodine, has been suggested. The aim of this study was to assess the relationship between pholcodine exposure and NMBA-related anaphylaxis.MethodsALPHO was a multicentre case-control study, comparing pholcodine exposure within a year before anaesthesia between patients with NMBA-related perioperative anaphylaxis (cases) and control patients with uneventful anaesthesia in France. Each case was matched to two controls by age, sex, type of NMBA, geographic area, and season. Pholcodine exposure was assessed by a self-administered questionnaire and pharmaceutical history retrieved from pharmacy records. The diagnostic values of anti-pholcodine and anti-quaternary ammonium specific IgE (sIgE) were also evaluated.ResultsOverall, 167 cases were matched with 334 controls. NMBA-related anaphylaxis was significantly associated with pholcodine consumption (odds ratio 4.2; 95% confidence interval 2.3–7.0) and occupational exposure to quaternary ammonium compounds (odds ratio 6.1; 95% confidence interval 2.7–13.6), suggesting that apart from pholcodine, other environmental factors can also lead to sensitisation to NMBAs. Pholcodine and quaternary ammonium sIgEs had a high negative predictive value (99.9%) but a very low positive predictive value (
Published: 2023

35. Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

Author: Jérémie Rosain, Anna-Lena Neehus, Jérémy Manry, Rui Yang, Jérémie Le Pen, Wassim Daher, Zhiyong Liu, Yi-Hao Chan, Natalia Tahuil, Özden Türel, Mathieu Bourgey, Masato Ogishi, Jean-Marc Doisne, Helena M. Izquierdo, Takayoshi Shirasaki, Tom Le Voyer, Antoine Guérin, Paul Bastard, Marcela Moncada-Vélez, Ji Eun Han, Taushif Khan, Franck Rapaport, Seon-Hui Hong, Andrew Cheung, Kathrin Haake, Barbara C. Mindt, Laura Pérez, Quentin Philippot, Danyel Lee, Peng Zhang, Darawan Rinchai, Fatima Al Ali, Manar Mahmoud Ahmad Ata, Mahbuba Rahman, Jessica N. Peel, Søren Heissel, Henrik Molina, Yasemin Kendir-Demirkol, Rasheed Bailey, Shuxiang Zhao, Jonathan Bohlen, Mathieu Mancini, Yoann Seeleuthner, Marie Roelens, Lazaro Lorenzo, Camille Soudée, María Elvira Josefina Paz, María Laura González, Mohamed Jeljeli, Jean Soulier, Serge Romana, Anne-Sophie L’Honneur, Marie Materna, Rubén Martínez-Barricarte, Mathieu Pochon, Carmen Oleaga-Quintas, Alexandre Michev, Mélanie Migaud, Romain Lévy, Marie-Alexandra Alyanakian, Flore Rozenberg, Carys A. Croft, Guillaume Vogt, Jean-François Emile, Laurent Kremer, Cindy S. Ma, Jörg H. Fritz, Stanley M. Lemon, András N. Spaan, Nicolas Manel, Laurent Abel, Margaret R. MacDonald, Stéphanie Boisson-Dupuis, Nico Marr, Stuart G. Tangye, James P. Di Santo, Qian Zhang, Shen-Ying Zhang, Charles M. Rice, Vivien Béziat, Nico Lachmann, David Langlais, Jean-Laurent Casanova, Philippe Gros, Jacinta Bustamante, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hannover Medical School [Hannover] (MHH), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Yong Loo Lin School of Medicine [Singapore], Hospital del Niño Jesus, San Miguel de Tucumán, Bezmiâlem Vakıf Üniversitesi, McGill University = Université McGill [Montréal, Canada], Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Curie [Paris], University of North Carolina System (UNC), Garvan Institute of medical research, The University of Sydney, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universidad de Antioquia = University of Antioquia [Medellín, Colombia], East China Normal University [Shangaï] (ECNU), Sidra Medicine [Doha, Qatar], 'Juan Pedro Garrahan' National Hospital of Pediatrics, Buenos Aires, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Hopital Saint-Louis [AP-HP] (AP-HP), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Hôpital Ambroise Paré [AP-HP], Université de Montpellier (UM), Howard Hughes Medical Institute (HHMI), The Laboratory of Human Genetics of Infectious Diseases is supported in part by grants from Inserm, Paris Cité University, the St. Giles Foundation, The Rockefeller University, the Center for Clinical and Translational Science (UL1TR001866), the National Center for Research Resources and the National Center for Advancing Sciences, the National Institutes of Health (NIH), (R01AI095983, R01AI088364, R01AI163029, and U19AI162568), the National Institute of Allergy and Infectious Diseases, the French National Research Agency (ANR) under the 'Investments for the future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS Nord-Sud (ANRS-COV05), ANRS (ECTZ170784-ANRS0073), GENVIR (ANR-20-CE93-003), GENMSMD (ANR-16-CE17-0005-01), AABIFNCOV (ANR-20-CO11-0001), GenMIS-C (ANR-21-COVR-0039), SUNLIVE (ANR-19-CE15-0012-01), MAFMACRO (ANR-22-CE92-0008) grants, Ecos-NORD (ECOS N°C19S01), the Fisher Center for Alzheimer's Research Foundation, the Meyer Foundation, the JPB Foundation, the European Union’s Horizon 2020 research and innovation program (824110, EASI-Genomics), the Square Foundation, Grandir–Fonds de solidarité pour l’Enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), and REACTing-INSERM. The Laboratory of Virology and Infectious Disease was supported in part by the NIH (R01AI091707-10 to C.M.R.). J.L.P. was supported by the Francois Wallace Monahan Postdoctoral Fellowship at The Rockefeller University and the European Molecular Biology Organization Long-Term Fellowship (ALTF 380-2018). N. Marr was supported by Sidra Medicine and the Qatar National Research Fund (NPRP9-251-3-045). The Yale Center for Mendelian Genomics (UM1HG006504) was funded by the National Human Genome Research Institute, the Yale GSP Coordinating Center (U24 HG008956), and the Yale High-Performance Computing Center (S10OD018521). This research was partly supported by Calcul Québec, Compute Canada Canadian Institutes of Health Research (CIHR) Project Grant to D. Langlais. (#168959) and a CIHR Foundation Grant (to P.G.). D. Langlais was also supported by an FRQS Chercheur-Boursier Junior 1 Award and the Calgary Foundation for Innovation John R. Evans Leaders Fund. P.G. is supported by a Distinguished James McGill Professorship award from McGill University. S.M.L is supported by the NIH: R01-AI103083 and R01-AI150095. J.R. was supported by poste d’accueil Inserm'. J.R., P.B., and T.L.V were supported by the MD-PhD program of the Imagine Institute by the Bettencourt Schueller Foundation. N.L received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (852178 grant), German Research Foundation,(DFG) under Germany’s Excellence Strategy—EXC 2155—project number 390874280 and REBIRTH 'Förderung aus Mitteln des Niedersächsischen Vorab'. A.-L.N. was supported by the international PhD program of the Imagine Institute, by the Bettencourt Schueller Foundation and the fin de thèse FRM program (FDT202204015102). R.Y. was supported by the Sackler Center for Biomedicine and Nutrition, the Shapiro-Silverberg Fund for the Advancement of Translational Research at the Center for Clinical and Translational Science of the Rockefeller University, and the Research Grant Program from the Immune Deficiency Foundation. D. Lee. was supported by FRMfellowship (FDM202006011282). C.S.M was supported by an Early-Mid Career Research Fellowship from the Department of Health of the New South Wales Government of Australia. S.G.T was supported by an NHMRC Leadership 3 Investigator Grant (1176665) and NHMRC grant (1113904). M.O. was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology, the Honjo International Scholarship Foundation, and the New York Hideyo Noguchi Memorial Society. This work was supported by grants from ANRS (ECTZ118797), Sidaction (20-2-AEQ-12822-2), and FRM (EQU202103012774) to N. Manel, and H.I. was supported by fellowships from Institut Curie, Seneca Foundation (20941/PD/18), and ANRS (ECTZ171453). A.N.S. was supported in part by the European Union’s Horizon 2020 research and innovation program (789645 Marie Sklodowska-Curie grant). Y.-H.C. is supported by an A∗STAR International Fellowship. J. Bohlen is an EMBO postdoctoral fellow. We thank the NIH Tetramer Core Facility (NTCF) for providing the 5-OP-RU-loaded MR1 tetramer, which was developed jointly with Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), ANR-19-CE15-0012,SUNLIVE,Variabilité structurale et fonctionnelle des lipides complexes chez les mycobactéries : de l'assemblage de la paroi à la physiopathologie et virulence(2019), ANR-22-CE92-0008,MAFMACRO,Genetic predisposition and the role of myeloid cells in the susceptibility to mycobacterial infection(2022), European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019), and TÜREL, ÖZDEN
Subjects: inborn errors of immunity, Temel Bilimler, [SDV]Life Sciences [q-bio], interferon-stimulated gene, Life Sciences, Molecular Biology and Genetics, Genel Biyokimya, Genetik ve Moleküler Biyoloji, IRF1, General Biochemistry, Genetics and Molecular Biology, Mycobacterium, macrophages, interferon-γ, Yaşam Bilimleri, viruses, Cytogenetic, Natural Sciences, Moleküler Biyoloji ve Genetik, Sitogenetik
Abstract: Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/β-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/β immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/β. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/β-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/β-dependent antiviral immunity.
Published: 2023

36. Omicron BA.1 breakthrough infection drives long-term remodeling of the memory B cell repertoire in vaccinated individuals

Author: Sokal, Aurélien, Barba-Spaeth, Giovanna, Hunault, Lise, Fernández, Ignacio, Broketa, Matteo, Meola, Annalisa, Fourati, Slim, Azzaoui, Imane, Vandenberghe, Alexis, Lagouge-Roussey, Pauline, Broutin, Manon, Roeser, Anais, Bouvier-Alias, Magali, Crickx, Etienne, Languille, Laetitia, Fournier, Morgane, Michel, Marc, Godeau, Bertrand, Gallien, Sébastien, Melica, Giovanna, Nguyen, Yann, Canoui-Poitrine, Florence, Noizat-Pirenne, France, Megret, Jérôme, Pawlotsky, Jean-Michel, Fillatreau, Simon, Reynaud, Claude-Agnès, Weill, Jean-Claude, Rey, Félix, Bruhns, Pierre, Mahévas, Matthieu, Chappert, Pascal, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC - CHU Henri Mondor, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Physiologie, physiopathologie et thérapeutique (ED 394), Sorbonne Université (SU), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Henri Mondor [Créteil], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Cochin [AP-HP], IMRB - CEPIA/'Clinical Epidemiology And Ageing : Geriatrics, Primary Care and Public Health' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Etablissement Français du Sang [Créteil], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and This work was funded by the CAPNET (Comité ad-hoc de pilotage national des essaisthérapeutiques et autres recherches, French government) and by the Fondation PrincesseGrace. Assistance Publique – Hôpitaux de Paris (AP-HP, Département de la Recherche Cli-nique et du Développement) was the promotor and sponsor of MEMO-COV-2. Work in theUnit of Structural Virology was funded by Institut Pasteur, Urgence COVID-19 FundraisingCampaign of Institut Pasteur. PB acknowledges funding from the Institut Pasteur and InsitutNational de la Santé et de la Recherche Médicale (INSERM). AS was supported by a Posted’accueil from INSERM.
Subjects: [SDV]Life Sciences [q-bio], [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract: SummaryHow infection by a viral variant showing antigenic drift impacts a preformed mature human memory B cell (MBC) repertoire remains an open question. Here, we studied the MBC response up to 6 months after Omicron BA.1 breakthrough infection in individuals previously vaccinated with three doses of mRNA vaccine. Longitudinal analysis, using single-cell multi-omics and functional analysis of monoclonal antibodies from RBD-specific MBCs, revealed that a BA.1 breakthrough infection mostly recruited pre-existing cross-reactive MBCs with limitedde novoresponse against BA.1-restricted epitopes. Reorganization of clonal hierarchy and new rounds of germinal center reaction, however, combined to maintain diversity and induce progressive maturation of the MBC repertoire against common Hu-1 and BA.1, but not BA.5-restricted, SARS-CoV-2 Spike RBD epitopes. Such remodeling was further associated with marked improvement in overall neutralizing breadth and potency. These findings have fundamental implications for the design of future vaccination booster strategies.
Published: 2023

37. Immune-Epithelial Cross Talk in Regeneration and Repair

Author: Laure Guenin-Mace, Piotr Konieczny, Shruti Naik, Immunobiologie et Thérapie - Immunobiology and Therapy, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), NYU Langone Health [New York], NIH 1DP2AR079173-01, R01-AI168462, Pew Foundation (00034119), and Packard Foundation
Subjects: stem cells, repair, regeneration, [SDV]Life Sciences [q-bio], Immunology, Immunology and Allergy, epithelium, immunity, inflammatory disease
Abstract: International audience; The epithelial tissues that line our body, such as the skin and gut, have remarkable regenerative prowess and continually renew throughout our lifetimes. Owing to their barrier function, these tissues have also evolved sophisticated repair mechanisms to swiftly heal and limit the penetration of harmful agents following injury. Researchers now appreciate that epithelial regeneration and repair are not autonomous processes but rely on a dynamic cross talk with immunity. A wealth of clinical and experimental data point to the functional coupling of reparative and inflammatory responses as two sides of the same coin. Here we bring to the fore the immunological signals that underlie homeostatic epithelial regeneration and restitution following damage. We review our current understanding of how immune cells contribute to distinct phases of repair. When unchecked, immune-mediated repair programs are co-opted to fuel epithelial pathologies such as cancer, psoriasis, and inflammatory bowel diseases. Thus, understanding the reparative functions of immunity may advance therapeutic innovation in regenerative medicine and epithelial inflammatory diseases.
Published: 2023

38. Microbiota-induced active translocation of peptidoglycan across the intestinal barrier dictates its within-host dissemination

Author: Richard Wheeler, Paulo André Dias Bastos, Olivier Disson, Aline Rifflet, Ilana Gabanyi, Julia Spielbauer, Marion Bérard, Marc Lecuit, Ivo Gomperts Boneca, Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall, Institut Pasteur [Paris] (IP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-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), Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Perception et Mémoire / Perception and Memory, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Microenvironnement et Immunité - Microenvironment and Immunity, Animalerie Centrale (plateforme) - Central Animal Facility (platform) (C2RA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Centre National de Référence Listeria - National Reference Center Listeria (CNR), Centre collaborateur de l'OMS Listeria / WHO Collaborating Centre Listeria (CC-OMS / WHO-CC), Institut Pasteur [Paris] (IP)-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This project has received funding from the Institut Carnot Pasteur Microbes & Santé, and the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no 665807. A.R. and I.G.B. laboratory were supported by Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10-LABX-62-IBEID). I.G.B. laboratory was also supported by the Investissement d’Avenir program (RHU Torino Lumière ANR-16-RHUS-0008), by the French National Research Agency (ANR-16-CE15-0021) and by R&D grants from Danone and MEIJI. Additional funding was provided by DIM1Health., We thank the UTechS PBI, a member of the France–BioImaging infrastructure network supported by the French National Research Agency (ANR-10–INSB–04, Investments for the future) for microscope usage and assistance. We thank the members of the Centre for Gnotobiology Platform of the Institut Pasteur (especially Thierry Angélique, Eddie Maranghi, Martine Jacob, and Marisa Gabriela Lopez Dieguez), and of the Institut Pasteur Central Animal Facility for all their assistance with animal studies. P.A.D.B. was part of the Pasteur-Paris University International PhD Program., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), ANR-16-CE15-0021,PG-Brain,Modulation de l'activité du cerveau par le peptidoglycan bactérien(2016), and European Project: 665807,H2020,H2020-MSCA-COFUND-2014,PASTEURDOC(2015)
Subjects: Multidisciplinary, gut microbiota, systemic trafficking, [SDV.BA]Life Sciences [q-bio]/Animal biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], peptidoglycan, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract: International audience; Peptidoglycan, the major structural polymer forming the cell wall of bacteria, is an important mediator of physiological and behavioral effects in mammalian hosts. These effects are frequently linked to its translocation from the intestinal lumen to host tissues. However, the modality and regulation of this translocation across the gut barrier has not been precisely addressed. In this study, we characterized the absorption of peptidoglycan across the intestine and its systemic dissemination. We report that peptidoglycan has a distinct tropism for host organs when absorbed via the gut, most notably by favoring access to the brain. We demonstrate that intestinal translocation of peptidoglycan occurs through a microbiota-induced active process. This process is regulated by the parasympathetic pathway via the muscarinic acetylcholine receptors. Together, this study reveals fundamental parameters concerning the uptake of a major microbiota molecular signal from the steady-state gut.
Published: 2023

39. Fast 2-photon stimulation using holographic patterns

Author: Maia Brunstein, Jules Lubetzki, Cédric Moutoussamy, Wei Li, Jérémie Barral, Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Institut des sciences biologiques (INSB-CNRS)
Subjects: [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics]
Abstract: Two decades after its introduction, optogenetics – a biological technique to control the activity of neurons or other cell types with light – remains a cutting edge and promising tool to study biological processes. Its increasing usage in research varies widely from causally exploring biological mechanisms and neural computations, to neurostimulation and sensory restauration. To stimulate neurons in the brain, a variety of approaches have been developed to generate precise spatiotemporal light patterns. Yet certain constrains still exists in the current optical techniques to activate a neuronal population with both cellular resolution and millisecond precision. Here, we describe an experimental setup allowing to stimulate a few tens of neurons in a plane at sub-millisecond rates using 2-photon activation. A liquid crystal on silicon spatial light modulator (LCoS-SLM) was used to generate spatial patterns in 2 dimensions. The image of the patterns was formed on the plane of a digital micromirror device (DMD) that was used as a fast temporal modulator of each region of interest. Using fluorescent microscopy and patch-clamp recording of neurons in culture expressing the light-gated ion channels, we characterized the temporal and spatial resolution of the microscope. We described the advantages of combining the LCoS-SLM with the DMD to maximize the temporal precision, modulate the illumination amplitude, and reduce background activation. Finally, we showed that this approach can be extended to patterns in 3 dimensions. We concluded that the methodology is well suited to address important questions about the role of temporal information in neuronal coding.
Published: 2023

40. Psychological and neuroscientific foundations of rhythms and timing

Author: Keith B. Doelling, Sophie K Herbst, Luc H. Arnal, Virginie van Wassenhove, Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Neuroimagerie cognitive - Psychologie cognitive expérimentale (UNICOG-U992), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay
Subjects: neural oscillations, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.PSYC]Cognitive science/Psychology, timing, music, prediction
Abstract: International audience; Cultural artefacts, such as dance and music, are characterized by temporal properties, broadly referred to as rhythms. The temporal structures that emerge when individuals synchronize their movements provide a sense of togetherness and common fate, even if individuals can readily tune in and out of this shared temporal space. In this chapter, we concisely discuss the endogenous and exogenous factors contributing to the emergence of brain rhythms and rhythmic behaviors, and how their interplay contributes to sophisticated forms of expressions in humans. The capacity for coupling and uncoupling voluntarily from external rhythms creates a potential tension between our environment (exogenously driven) and our internal state (endogenously driven) that can be exploited for artistic benefit, in the form of surprisal.
Published: 2023

41. Sec22b is a critical and non-redundant regulator of plasma cell maintenance

Author: Amélie Bonaud, Laetitia Gargowitsch, Simon M. Gilbert, Elanchezhian Rajan, Pablo Canales-Herrerias, Daniel Stockholm, Nabila F. Rahman, Mark O. Collins, Hakan Taskiran, Danika L. Hill, Andres Alloatti, Nagham Alouche, Stéphanie Balor, Vanessa Soldan, Daniel Gillet, Julien Barbier, Françoise Bachelerie, Kenneth G. C. Smith, Julia Jellusova, Pierre Bruhns, Sebastian Amigorena, Karl Balabanian, Michelle A. Linterman, Andrew A. Peden, Marion Espéli, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Inflammation, microbiome, immunosurveillance (MI2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, University of Cambridge [UK] (CAM), University of Sheffield [Sheffield], Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), School of Psychology [Cardiff University], Cardiff University, Technische Universität München = Technical University of Munich (TUM), Max Planck Institute of Immunobiology and Epigenetics (MPI-IE), Max-Planck-Gesellschaft, The Babraham Institute [Cambridge, UK], Monash University [Melbourne], Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidad Nacional de Rosario [Santa Fe], Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ANR-19-CE15-0019,PC-SEC,Impact des SNARE sur la biologie des plasmocytes(2019), ANR-14-ACHN-0008,AUTO-PLASMO,Analyse integrative de la biologie des plasmocytes normaux et pathologiques(2014), ANR-17-CE14-0019,OSTEOVALYMPH,Autocrinie et paracrinie de l'axe de signalisation CXCL12/CXCR4-CXCR7 dans la niche ostéo-vasculaire: impact sur la spécification et l'engagement lymphoïde des cellules souches hématopoïétiques(2017), ANR-18-CE15-0001,Autoimmuni-B,Etude de la rupture de tolérance dans une maladie humaine autoimmune médiée par les lymphocytes B(2018), The study was supported by the Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LabEx LERMIT) (M.E. and K.B.), an ANR JCJC grant (ANR-19-CE15-0019-01), an ANR @RAction grant (ANR-14-ACHN-0008), a 'Fondation ARC pour la recherche sur le cancer' grant (P JA20181208173), and a grant from IdEx Université Paris-Cité (ANR-18-IDEX-0001) to M.E., and an ANR PRC grant (ANR-17-CE14-0019) and an INCa grant (PRT-K 2017) to K.B. P.B. acknowledges funding from the French National Research Agency grant ANR-18-CE15-0001 project Autoimmuni-B, by the Institut Carnot Pasteur Microbes et Santé grant ANR-11-CARN-0017-01, the Institut Pasteur, and the Institut National de la Santé et de la Recherche Médicale (INSERM). M.A.L. is supported by Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0427, BBS/E/B/000C0428, and the Campus Capability Core Grant to the Babraham Institute). A.A.P. and M.O.C. were supported by a grant from the Biotechnology and Biological Sciences Research Council (BB/L022389/1). D.L.H. is supported by a National Health and Medical Research Council Australia Early-Career Fellowship (APP1139911). N.A. was supported by a PhD fellowship from the French Ministry for education and by a fourth year PhD fellowship from the 'Fondation ARC pour la recherche sur le cancer.' P.C.-H. was supported partly by a stipend from the Pasteur-Paris University (PPU) International PhD program, and by a fellowship from the French Fondation pour la Recherche Médicale (FRM). K.G.C.S. was supported by the Wellcome Trust (Programme Grant Number 083650/Z/07/Z). J.J’s research is supported by the German Research Foundation project number: 419193696 and through the CRC1335. H.T. is supported through the graduate school of the Max Planck Institute for Immunobiology and Epigenetics (IMPRS-IE) and through the CRC1335. The 'EMiLy' U1160 INSERM unit is a member of the OPALE Carnot institute, The Organization for Partnerships in Leukemia (Institut Carnot OPALE, Institut de Recherche Saint-Louis, Hôpital Saint-Louis, Paris, France. Web: www.opale.org. Email: contact@opale.org)., ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), Bonaud, Amélie [0000-0002-4153-9171], Rajan, Elanchezhian [0000-0002-6257-3678], Canales-Herrerias, Pablo [0000-0002-1865-6476], Stockholm, Daniel [0000-0002-5069-5256], Collins, Mark O [0000-0002-7656-4975], Taskiran, Hakan [0000-0002-2690-3887], Alloatti, Andres [0000-0003-0555-0653], Gillet, Daniel [0000-0003-0477-3599], Bruhns, Pierre [0000-0002-4709-8936], Balabanian, Karl [0000-0002-0534-3198], Linterman, Michelle A [0000-0001-6047-1996], Peden, Andrew A [0000-0003-0144-7712], Espéli, Marion [0000-0001-5005-1664], and Apollo - University of Cambridge Repository
Subjects: R-SNARE Proteins, mitochondria, Mice, endoplasmic reticulum, Multidisciplinary, plasma cell, SNARE, antibody, [SDV]Life Sciences [q-bio], Plasma Cells, Animals, Biological Transport, SNARE Proteins
Abstract: Despite the essential role of plasma cells in health and disease, the cellular mechanisms controlling their survival and secretory capacity are still poorly understood. Here, we identified the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) Sec22b as a unique and critical regulator of plasma cell maintenance and function. In the absence of Sec22b, plasma cells were hardly detectable and serum antibody titers were dramatically reduced. Accordingly, Sec22b -deficient mice fail to mount a protective immune response. At the mechanistic level, we demonstrated that Sec22b contributes to efficient antibody secretion and is a central regulator of plasma cell maintenance through the regulation of their transcriptional identity and of the morphology of the endoplasmic reticulum and mitochondria. Altogether, our results unveil an essential and nonredundant role for Sec22b as a regulator of plasma cell fitness and of the humoral immune response.
Published: 2023

42. V(D)J Recombination: Orchestrating Diversity Without Damage

Author: C. Lescale, L. Deriano, Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Ralph A. Bradshaw, Gerald W. Hart, and Philip D. Stahl
Subjects: Genome instability, Genetics, Genomic instability, DNA repair, [SDV]Life Sciences [q-bio], V(D)J recombination, Biology, DNA damage response, Antigen receptor diversification, Recombination activating genes (RAGs) and V(D)J recombination, Immune system, Double-strand break, Leukemia and lymphoma, Immunodeficiency, Neoplastic transformation, Epigenetics, Lymphocyte, Gene, Recombination, NHEJ, Cancer
Abstract: International audience; V(D)J recombination assembles immunoglobulin and T-cell receptor genes from the preexisting variable (V), diversity (D), and joining (J) gene segments by a cut and paste mechanism. While this receptor diversification strategy enables efficient immune responses against pathogens, it also poses a constant threat to the genome integrity. Tight regulation of this process at multiple levels is therefore critical to prevent genomic instability and neoplastic transformation. In this article, we discuss the temporal and spatial regulation of V(D)J recombination, in addition to the molecular mechanisms that regulate this process. Finally, we discuss the implication of V(D)J recombination in malignancies of the immune system. “RAGs are the end-point of the strategies developed through evolution to achieve the anticipatory “Promethean” recognition of all universal molecular forms”. – A.A. de Freitas, Tractus Immuno-Logicus.
Published: 2023

43. Oxidized hemoglobin triggers polyreactivity and autoreactivity of human IgG via transfer of heme

Author: Cyril Planchais, Remi Noe, Marie Gilbert, Maxime Lecerf, Srini V. Kaveri, Sébastien Lacroix-Desmazes, Lubka T. Roumenina, Jordan D. Dimitrov, Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM, France) and by grants from Agence Nationale de la Recherche (ANR-13-JCV1-006-01) and from the European Research Council (Project CoBABATI ERC-StG-678905), both to J.D.D., ANR-13-JSV1-0006,COBIG,Rôle physiopathologique des anticorps liant les co-facteurs(2013), European Project: 678905,H2020-EU.1.1., and ERC-StG-2015,CoBABATI(2016)
Subjects: [SDV]Life Sciences [q-bio], Medicine (miscellaneous), General Agricultural and Biological Sciences, General Biochemistry, Genetics and Molecular Biology
Abstract: Intravascular hemolysis occurs in diverse pathological conditions. Extracellular hemoglobin and heme have strong pro-oxidative and pro-inflammatory potentials that can contribute to the pathology of hemolytic diseases. However, many of the effects of extracellular hemoglobin and heme in hemolytic diseases are still not well understood. Here we demonstrate that oxidized hemoglobin (methemoglobin) can modify the antigen-binding characteristics of human immunoglobulins. Thus, incubation of polyclonal or some monoclonal human IgG in the presence of methemoglobin results in an appearance of binding reactivities towards distinct unrelated self-proteins, including the protein constituent of hemoglobin i.e., globin. We demonstrate that a transfer of heme from methemoglobin to IgG is indispensable for this acquisition of antibody polyreactivity. Our data also show that only oxidized form of hemoglobin have the capacity to induce polyreactivity of antibodies. Site-directed mutagenesis of a heme-sensitive human monoclonal IgG1 reveals details about the mechanism of methemoglobin-induced antigen-binding polyreactivity. Further here we assess the kinetics and thermodynamics of interaction of a heme-induced polyreactive human antibody with hemoglobin and myoglobin. Taken together presented data contribute to a better understanding of the functions of extracellular hemoglobin in the context of hemolytic diseases.
Published: 2023
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44. Conditional neutrophil depletion challenges their contribution to mouse models of anaphylaxis

Author: Julien Stackowicz, Caitlin M. Gillis, Ophélie Godon, Bruno Iannascoli, Eva Conde, Edouard Leveque, William P. M. Worrall, Stephen J. Galli, Pierre Bruhns, Laurent L. Reber, Friederike Jönsson, Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Collège Doctoral, Sorbonne Université (SU), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, This work was supported by a Jeunes Chercheuses/Jeunes Chercheurs grant from the Agence National de la Recherche (ANR-16-CE15-0012, to FJ). The Phenomin project receives funds from the ANR under the framework 'Investissements d'Avenir' labelled ANR-10-INBS-07 PHENOMIN. PB acknowledges support from the European Research Council (ERC)–Seventh Framework Program (ERC-2013-CoG 616,050), Institut Pasteur and INSERM (Institut National de la Santé et de la Recherche Médicale), SJG from NIH grant R01 AI165373, CMG was supported by a stipend from the Pasteur – Paris University (PPU) International PhD program and by the Institut Carnot Pasteur Maladies Infectieuses, and LLR from an ATIP-Avenir grant from the INSERM and the Fondation pour la Recherche Médicale (FRM EQU202103012566)., ANR-16-CE15-0012,PlanA,Rôle des plaquettes et leurs interactions dans les réactions anaphylactiques(2016), ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010), and European Project: 616050,EC:FP7:ERC,ERC-2013-CoG,MYELOSHOCK(2014)
Subjects: [SDV]Life Sciences [q-bio], Immunology, Immunology and Allergy
Abstract: International audience; No abstract available
Published: 2023

45. Genetic heterogeneity in GJB2, COL4A3, ATP6V1B1 and EDNRB variants detected among hearing impaired families in Morocco

Author: Imane AitRaise, Ghita Amalou, Amale Bousfiha, Hicham Charoute, Hassan Rouba, Houria Abdelghaffar, Crystel Bonnet, Christine Petit, Adbelhamid Barakat, Institut Pasteur du Maroc, Réseau International des Instituts Pasteur (RIIP), University Hassan II [Casablanca], Génétique et Physiologie de l'Audition, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Petit, Christine
Subjects: Collagen Type IV, Vacuolar Proton-Translocating ATPases, MESH: Mutation, MESH: Pedigree, Hearing Loss, Sensorineural, [SDV]Life Sciences [q-bio], MESH: Vacuolar Proton-Translocating ATPases, MESH: Deafness, Deafness, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Moroccan patients, Autoantigens, Connexins, Genetic Heterogeneity, Hearing, MESH: Connexin 26, Genetics, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, MESH: Hearing, MESH: Hearing Loss, MESH: Collagen Type IV, Molecular Biology, MESH: Humans, Whole exome sequencing, MESH: Genetic Heterogeneity, Hearing loss, General Medicine, Receptor, Endothelin B, MESH: Receptor, Endothelin B, Pedigree, MESH: Connexins, Connexin 26, [SDV] Life Sciences [q-bio], Morocco, MESH: Autoantigens, MESH: Hearing Loss, Sensorineural, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, MESH: Morocco, Mutation
Abstract: International audience; Background: Deafness is the most prevalent human sensorineural defect. It may occur as a result of an external auditory canal involvement, or a deficiency in the sound conduction mechanism, or an impairment of the cochlea, the cochlear nerve or central auditory perception. The genetic causes are the most common, as approximately 70% of hearing disorders are of hereditary origin, divided into two groups, syndromic (associated with other symptoms) and no syndromic (isolated deafness).Methods: A whole exome sequencing was performed to identify the genetic cause of hearing loss in six Moroccan families and Sanger sequencing was used to validate mutations in these genes.The results: The results of four out of the six families revealed four genetic variants in the genes GJB2, COL4A3, ATP6V1B1 and EDNRB responsible for non-syndromic and syndromic hearing loss. Multiple Bioinformatics programs and molecular modelling predicted the pathogenic effect of these mutations.Conclusions: We identified in Moroccan deaf patients four homozygous mutations. These results show the importance of whole exome sequencing to identify pathogenic mutations in heterogeneous disorders with multiple genes responsible.
Published: 2022

46. The anti‐FcεRI antibody MAR‐1 depletes basophils and cross‐reacts with myeloid cells through its Fc portion

Author: William P. M. Worrall, Jasper B. J. Kamphuis, Julien Stackowicz, Aurélie Mougel, Emilie Mauré, Cyprien Pecalvel, Sébastien Brûlé, Pierre Bruhns, Laurent Guilleminault, Laurent L. Reber, Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Sorbonne Université (SU), Biophysique Moléculaire (plateforme) - Molecular Biophysics (platform), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), ANR-18-CE18-0023,AllergyVACS,Développement d'un vaccin thérapeutique pour les maladies allergiques(2018), and ANR-20-CE15-0026,AsthmAb,Role des IgE humaines et de leur récepteur FceRI dans l'asthme et sa potentialisation par l'obésité(2020)
Subjects: basophil, Leukocyte Count, Receptors, IgE, Immunology, anaphylaxis, Humans, Immunology and Allergy, IgE, Mast Cells, Immunoglobulin E, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Cell Degranulation, Basophils
Abstract: International audience; In humans, the high-affinity IgE receptor FcεRI is expressed as a tetramer in mast cells (MCs) and basophils, and as a trimer in additional myeloid cell populations, including monocytes, macrophages, dendritic cells (DCs), and Langerhans cells.1 In mice, the expression profile of FcεRI is more debatable. Some studies report FcεRI+ macrophages and DCs.2 However, recent data indicate that the anti-FcεRI mAb (clone MAR-1) used in all these studies can recognize myeloid cells in an FcεRI-independent manner, and cross-reacts with FcγRI and FcγRIV.3, 4 Since MAR-1 has been extensively used in vivo to assess the role of FcεRI and to deplete basophils,5 the off-target effects of this mAb raise concerns regarding some of the conclusions made in prior studies. We thus decided to assess by which mechanism MAR-1 cross-reacts with FcγRs, and whether this cross-reactivity accounts for some of the functions previously attributed to FcεRI and/or basophils.
Published: 2022

47. APOBEC3C S188I Polymorphism Enhances Context-Specific Editing of Hepatitis B Virus Genome

Author: Pierre Khalfi, Rodolphe Suspène, Vincent Caval, Valérie Thiers, Guillaume Beauclair, Agnès Marchio, Claudine Bekondi, Marie Amougou Atsama, Serge Magloire Camengo-Police, Dominique Noah Noah, Richard Njouom, Hervé Blanc, Thomas Vallet, Marco Vignuzzi, Pascal Pineau, Jean Pierre Vartanian, Virologie (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Département de Virologie - Department of Virology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur de Bangui, Réseau International des Instituts Pasteur (RIIP), Centre Pasteur du Cameroun, Hôpital Central de Yaoundé [Yaoundé], Hôpital de l'Amitié [Bangui], Populations virales et Pathogenèse - Viral Populations and Pathogenesis, This work was supported by the Institut Pasteur (grants to R. S., V. C., V. T., G. B., H. B., T. V., M. V., and J. P. V.), Institut Pasteur International Network (Action Concertée Inter-Pasteurienne grant number 17-2010 and Grant Dedonder to C. B., M. A. A., S. M. C. P., D. N. N., and R. N.), and and Ligue Contre le Cancer (Equipe Labélisée d’Anne Dejean to A. M. and P. P.). P. K. was supported by the Ligue Contre le Cancer.
Subjects: Hepatitis B virus, editing, nucleotide context, Genome, Viral, Hepatitis B, Polymorphism, Single Nucleotide, patients, polymorphism, Infectious Diseases, Cytidine Deaminase, Africa, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Humans, APOBEC3C, Immunology and Allergy
Abstract: Single-nucleotide polymorphism in APOBEC3C (resulting in a serine to isoleucine in position 188) is present in approximately 10% of African populations and greatly enhances restriction against human immunodeficiency virus-1 and simian immunodeficiency virus by improving dimerization and DNA processivity of the enzyme. In this study, we demonstrated in culture and in infected patients that hepatitis B virus (HBV) could be edited by APOBEC3CS188I. Using next-generation sequencing, we demonstrated that APOBEC3CS188I led to enhanced editing activity in 5ʹTpCpA→5ʹTpTpA context. This constitutes a new hallmark of this enzyme, which could be used to determine its impact on HBV or nuclear DNA.
Published: 2022

48. Premature commitment to uncertain decisions during human NMDA receptor hypofunction

Author: Alexandre Salvador, Luc H. Arnal, Fabien Vinckier, Philippe Domenech, Raphaël Gaillard, Valentin Wyart, Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), GHU Paris Psychiatrie et Neurosciences, Laboratoire de Neurosciences Cognitives & Computationnelles (LNC2), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité (UPCité), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Motivation, cerveau et comportement = Motivation, Brain and Behavior [ICM Paris] (MBB), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neurophysiologie des comportements répétitifs [ICM Paris], Pôle de psychiatrie et d'addictologie des Hôpitaux Universitaires Henri-Mondor [Créteil], Centre hospitalier universitaire Henri-Mondor [Créteil], Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), This work was supported by a starting grant from the European Research Council (ERC-StG-759341) awarded to V.W., a junior researcher grant from the French National Research Agency (ANR-14-CE13-0028-01) awarded to V.W., a young investigator award from the Fyssen Foundation to V.W., a donation from the Schizo-oui association to R.G., and a starting grant from the Institut de Psychiatrie et de Neurosciences de Paris awarded to R.G. A.S. was funded by a doctoral fellowship from the Fondation pour la Recherche Médicale., ANR-14-CE13-0028,SUB-DECISION,Sous-optimalité de la prise de décision humaine : redéfinir les modèles du choix en termes en contraintes neurobiologiques(2014), European Project: 759341,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC),ERC-2017-STG,OPTIMIZERR(2018), Gestionnaire, Hal Sorbonne Université, Appel à projets générique - Sous-optimalité de la prise de décision humaine : redéfinir les modèles du choix en termes en contraintes neurobiologiques - - SUB-DECISION2014 - ANR-14-CE13-0028 - Appel à projets générique - VALID, and Errors as cost-optimizing decisions? Redefining the origin and nature of human decision errors in light of associated neural computations - OPTIMIZERR - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)2018-05-01 - 2023-04-30 - 759341 - VALID
Subjects: Adult, Male, Time Factors, Psychometrics, Science, Decision Making, Decision, General Physics and Astronomy, Receptors, N-Methyl-D-Aspartate, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Cognition, 0302 clinical medicine, Task Performance and Analysis, Human behaviour, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030304 developmental biology, 0303 health sciences, Multidisciplinary, Uncertainty, Brain, Bayes Theorem, Electroencephalography, General Chemistry, Female, Ketamine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cues, 030217 neurology & neurosurgery
Abstract: Making accurate decisions based on unreliable sensory evidence requires cognitive inference. Dysfunction of n-methyl-d-aspartate (NMDA) receptors impairs the integration of noisy input in theoretical models of neural circuits, but whether and how this synaptic alteration impairs human inference and confidence during uncertain decisions remains unknown. Here we use placebo-controlled infusions of ketamine to characterize the causal effect of human NMDA receptor hypofunction on cognitive inference and its neural correlates. At the behavioral level, ketamine triggers inference errors and elevated decision uncertainty. At the neural level, ketamine is associated with imbalanced coding of evidence and premature response preparation in electroencephalographic (EEG) activity. Through computational modeling of inference and confidence, we propose that this specific pattern of behavioral and neural impairments reflects an early commitment to inaccurate decisions, which aims at resolving the abnormal uncertainty generated by NMDA receptor hypofunction., In uncertain conditions, people make accurate decisions by considering multiple pieces of information. Here, the authors show that pharmacological n-methyl-d-aspartate (NMDA) receptor hypofunction is associated with elevated uncertainty and premature decisions based on unreliable evidence.
Published: 2022

49. A medullary centre for lapping in mice

Author: Dempsey, Bowen, Sungeelee, Selvee, Bokiniec, Phillip, Chettouh, Zoubida, Diem, Séverine, Autran, Sandra, Harrell, Evan R., Poulet, James F. A., Birchmeier, Carmen, Carey, Harry, Genovesio, Auguste, McMullan, Simon, Goridis, Christo, Fortin, Gilles, Brunet, Jean-François, Fortin, Gilles, Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Macquarie University [Sydney], ANR-17-CE16-0006,HEARTBRAIN,Développement et Physiologie des Neurones Intrinsèques du Cœur(2017), ANR-19-CE16-0029,HOMORESP,Résaux neuronaux homotypiques du contrôle respiratoire(2019), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS 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 National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS 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 National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Macquarie University, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: Male, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Science, Action Potentials, Neural circuits, behavioral disciplines and activities, Article, Mice, Tongue, Animals, Central pattern generators, Homeodomain Proteins, Mice, Knockout, Motor Neurons, Medulla Oblongata, Reticular Formation, digestive, oral, and skin physiology, fungi, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, food and beverages, Feeding Behavior, Jaw, Female, Function and Dysfunction of the Nervous System, Brain Stem, Transcription Factors
Abstract: It has long been known that orofacial movements for feeding can be triggered, coordinated, and often rhythmically organized at the level of the brainstem, without input from higher centers. We uncover two nuclei that can organize the movements for ingesting fluids in mice. These neuronal groups, IRtPhox2b and Peri5Atoh1, are marked by expression of the pan-autonomic homeobox gene Phox2b and are located, respectively, in the intermediate reticular formation of the medulla and around the motor nucleus of the trigeminal nerve. They are premotor to all jaw-opening and tongue muscles. Stimulation of either, in awake animals, opens the jaw, while IRtPhox2b alone also protracts the tongue. Moreover, stationary stimulation of IRtPhox2b entrains a rhythmic alternation of tongue protraction and retraction, synchronized with jaw opening and closing, that mimics lapping. Finally, fiber photometric recordings show that IRtPhox2b is active during volitional lapping. Our study identifies one of the subcortical nuclei underpinning a stereotyped feeding behavior., Orofacial movements for feeding can be triggered, coordinated and rhythmically organised at the level of the brainstem. Here, the authors show two nuclei can organise the stereotyped movements for ingesting fluids in mammals, these neuronal groups are marked by expression of Phox2b and are located in the intermediate reticular formation of the medulla and around the motor nucleus of the trigeminal nerve.
Published: 2021

50. A live measles-vectored COVID-19 vaccine induces strong immunity and protection from SARS-CoV-2 challenge in mice and hamsters

Author: Frantz, Phanramphoei N., Barinov, Aleksandr, Ruffié, Claude, Combredet, Chantal, Najburg, Valérie, de Melo, Guilherme Dias, Larrous, Florence, Kergoat, Lauriane, Teeravechyan, Samaporn, Jongkaewwattana, Anan, Billon-Denis, Emmanuelle, Tournier, Jean-Nicolas, Prot, Matthieu, Levillayer, Laurine, Conquet, Laurine, Montagutelli, Xavier, Tichit, Magali, Hardy, David, Fernandes, Priyanka, Strick-Marchand, Hélène, Di Santo, James, Simon-Lorière, Etienne, Bourhy, Hervé, Tangy, Frédéric, Laboratoire d’innovation : vaccins – Innovation lab : vaccines, Institut Pasteur [Paris], Université de Paris (UP), National Center for Genetic Engineering and Biotechnology [Thailand] (BIOTEC), National Science and Technology Development Agency [Bangkok] (NSTDA), VIROxIS [Villejuif], Institut Gustave Roussy (IGR), Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Institut de Recherche Biomédicale des Armées (IRBA), Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Génétique de la souris - Mouse Genetics, Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris]-Université de Paris (UP), Immunité Innée - Innate Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Funding for 'Outbreak Response to Novel Coronavirus (COVID-19): Development of a vaccine against novel coronavirus SARS-CoV-2 using the clinical Phase III measles vector technology' project was provided by the Coalition for Epidemic Preparedness Innovations (CEPI). The development of the mouse-adapted MacO3 virus was funded by the ANR-20-COVI-0028-01 grant program. P.N.F. was supported by the ANR-18-CE17-0004-01 programme, Recherche translationnelle en santé. Part of this work was supported by Institut Pasteur TASK FORCE SARS COV2 (NicoSARS and NeuroCovid projects)., We thank Anastassia Komarova, Vincent Enouf and Sylvie Van Der Werf from the RNA Viruses Molecular Genetics Unit of Institut Pasteur for helpful discussions and SARS-Cov-2 virus information. We thank Maud Vanpeene and Vincent Enouf from the Mutualized Platform of Microbiology, Pasteur International Bioresources Network for viral sequencing. We thank Victoire Perraud and Simon Bonas from the Lyssavirus Epidemiology and Neuropathology Unit for their help with animal experiments and RNA extraction. We thank Audrey Ferrier, Annabelle Garnier, and Laurence Cheutin from the Armed Forces Biomedical Research Institute (IRBA) for handling the serums cohort from SARS-Cov-2 convalescent patients., ANR-20-COVI-0028,HuMoCID,Développement de modèles murins de COVID-19(2020), ANR-18-CE17-0004,ComboVaxEm,Des vaccins combinés contre les infections virales émergentes(2018), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hardy, David, Développement de modèles murins de COVID-19 - - HuMoCID2020 - ANR-20-COVI-0028 - COVID-19 - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Des vaccins combinés contre les infections virales émergentes - - ComboVaxEm2018 - ANR-18-CE17-0004 - AAPG2018 - VALID, and Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)
Subjects: Male, COVID-19 Vaccines, Live attenuated vaccines, [SDV]Life Sciences [q-bio], Science, Genetic Vectors, Measles Vaccine, Immunization, Secondary, Antibodies, Viral, Article, Adenoviridae, Mice, Cricetinae, Animals, Mesocricetus, SARS-CoV-2, Immunity, COVID-19, Antibodies, Neutralizing, [SDV] Life Sciences [q-bio], Viral infection, Spike Glycoprotein, Coronavirus, Cytokines, Female, Immunization
Abstract: Several COVID-19 vaccines have now been deployed to tackle the SARS-CoV-2 pandemic, most of them based on messenger RNA or adenovirus vectors.The duration of protection afforded by these vaccines is unknown, as well as their capacity to protect from emerging new variants. To provide sufficient coverage for the world population, additional strategies need to be tested. The live pediatric measles vaccine (MV) is an attractive approach, given its extensive safety and efficacy history, along with its established large-scale manufacturing capacity. We develop an MV-based SARS-CoV-2 vaccine expressing the prefusion-stabilized, membrane-anchored full-length S antigen, which proves to be efficient at eliciting strong Th1-dominant T-cell responses and high neutralizing antibody titers. In both mouse and golden Syrian hamster models, these responses protect the animals from intranasal infectious challenge. Additionally, the elicited antibodies efficiently neutralize in vitro the three currently circulating variants of SARS-CoV-2., Here the authors generate a measles virus-based vaccine expressing SARSCoV-2 spike protein and show immunogenicity and protection in mice and hamsters, including neutralization of circulating variants of concerns in vitro.
Published: 2021

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