Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Regulation du cycle cellulaire : roles respectifs de la synthese et de la phosphorylation des proteines

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Rôle de la traduction locale de CaMKIIalpha dans la plasticité et le développement du bulbe olfactif adulte

Thèse Marie Néant-Fery - Résumé La traduction locale dendritique de CaMKIIa a été mise en évidence notamment dans l hippocampe (HC), où elle contribue à la plasticité synaptique et à l élaboration de certaines formes de mémoire. Nous avons étudié son rôle dans le bulbe olfactif (BO) de la souris, région du cerveau hautement plastique en réponse à l activité olfactive. Nous avons montré que l ARNm de CaMKIIa est localisé dans les dendrites et enrichi aux synapses des cellules granulaires (CG), où il peut être traduit localement. Sa localisation synaptique dépend de l activité olfactive et semble être régulée par les récepteurs NMDA. Dans des souris mutantes dépourvues du 3 UTR de l ARNm de CaMKIIa (critique pour la localisation dendritique du messager), cette localisation dendritique est dramatiquement réduite, et ces souris présentent des défauts d apprentissage olfactif. Cette étude indique donc un rôle nouveau pour la traduction locale de CaMKIIa dans la plasticité olfactive. Le BO possède de plus une forme de métaplasticité conférée par le renouvellement permanent des CG chez l adulte. Nous avons utilisé cette neurogénèse adulte dans le BO comme un nouveau modèle d étude de la traduction locale de CaMKIIa. Dans le GC néoformées, l ARNm de CaMKIIa est également transporté dans les dendrites et enrichi aux synapses. Chez les mutants 3 UTR, ces néoneurones présentent des anomalies de développement de l arborisation dendritique. Les conséquences fonctionnelles de ces anomalies restent à être élucidées, mais cette seconde étude révèle pour la première fois le rôle de la traduction locale de CaMKIIa dans le développement dendritiquePARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Etude des gènes cibles du calcium impliqués dans la détermination cellulaire au cours de l'embryogénèse précoce

Chez l'embryon de Xénope pendant la gastrulation, une augmentation de la concentration intracellulaire en calcium est nécessaire et suffisante pour engager les cellules ectodermiques dorsales vers la destinée neurale. Or la relation entre cette variation calcique et l'expression des gènes neuraux précoces est inconnue. De tels gènes, isolés par une approche soustractive sont induits suite à une variation calcique et par noggin: xPRMT1b, une arginine N-méthyltransférase I et xMLP, un effecteur du complexe calcium-calmoduline. Ils s'expriment au niveau des territoires présomptifs neuraux. L'étude fonctionnelle de xPRMT1b montre que cette enzyme est nécessaire au développement des structures neurales antérieures, et l'intègre dans la voie de signalisation neurale contrôlée par le signal calcique. Le calcium en coordination avec les autres voies pro-neurales serait un signal instructif, permettant un contrôle spatio-temporel de la compétence neurale via l'expression de gènes pro-neuraux.During gastrulation, an increase in intracellular Ca2+ is both necessary and sufficient to commit the ectoderm to a neural fate in Xenopus embryos. However, the relationship between this Ca2+ increase and the expression of early neural genes has yet to be defined. Using a subtractive library, we isolated such genes characterised by an expression induced both by an increase in calcium and by the dorsalizing factor noggin. We specifically focused on xPRMT1b, an arginine N-methyltransferase and xMLP, a calcium-calmodulin effector. During embryogenesis, these genes are expressed in neural territories. Functional analysis of xPRMT1b showed that this enzyme is required for correct anterior neural development. We have then included xPRMT1b in the neural pathway triggered by calcium signalling. Thus, calcium, in addition with the other pro-neural pathways, is an instructive signal which contributes to the spatio-temporal control of neural competence.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

The RNA-binding protein Xp54nrb isolated from a Ca2+-dependent screen is expressed in neural structures during Xenopus laevis development

In amphibian embryos, calcium (Ca2+) signalling is a necessary and sufficient event to induce neural fate. Transient elevations of [Ca2+]i are recorded in neural tissue precursor cells in whole embryos during gastrulation. Using a subtractive cDNA library between control ectoderm (animal caps) and ectoderm induced toward a neural fate by Ca2+ release, we have isolated several Ca2+-induced target genes. Among the isolated genes, Xp54nrb encodes a protein which exhibits the RRM domains characteristic of RNA binding proteins, and is implicated in pre-mRNA splicing steps. Here we show that the Xp54nrb transcripts are expressed throughout early developmental stages, specifically in the neural and sensorial territories and that Xp54nrb could be involved in anterior neural patterning

TRPP2-dependent Ca2+ signaling in dorso-lateral mesoderm is required for kidney field establishment in Xenopus

International audienceIn Xenopus laevis embryos, kidney field specification is dependent on retinoic acid (RA) and coincides with a dramatic increase of Ca2+ transients, but the role of Ca2+ signaling in the kidney field is unknown. Here, we identify TRPP2, a member of the transient receptor potential (TRP) superfamily of channel proteins encoded by the pkd2 gene, as a central component of Ca2+ signaling in the kidney field. TRPP2 is strongly expressed at the plasma membrane where it might regulate extracellular Ca2+ entry. Knockdown of pkd2 in the kidney field results in the downregulation of pax8, but not of other kidney field genes (lhx1, osr1 and osr2). We further show that inhibition of Ca2+ signaling with an inducible Ca2+ chelator also causes downregulation of pax8, and that pkd2 knockdown results in a severe inhibition of Ca2+ transients in kidney field explants. Finally, we show that disruption of RA results both in an inhibition of intracellular Ca2+ signaling and of TRPP2 incorporation into the plasma membrane of kidney field cells. We propose that TRPP2-dependent Ca2+ signaling is a key component of pax8 regulation in the kidney field downstream of RA-mediated non-transcriptional control of TRPP2

Calcium signaling orchestrates glioblastoma development: Facts and conjunctures

International audienceWhile it is a relatively rare disease, glioblastoma multiform (GBM) is one of the more deadly-adult cancers. Following current interventions, the tumor is never eliminated whatever the treatment performed; whether it is radiotherapy, chemotherapy, or surgery. One hypothesis to explain this poor outcome is the ``cancer stem cell'' hypothesis. This concept proposes that a minority of cells within the tumor mass share many of the properties of adult neural stem cells and it is these that are responsible for the growth of the tumor and its resistance to existing therapies. Accumulating evidence suggests that Ca2+ might also be an important positive regulator of tumorigenesis in GBM, in processes involving quiescence, maintenance, proliferation, or migration. Glioblastoma tumors are generally thought to develop by co-opting pathways that are involved in the formation of an organ. We propose that the cells initiating the tumor, and subsequently the cells of the tumor mass, must hijack the different checkpoints that evolution has selected in order to prevent the pathological development of an organ. In this article, two main points are discussed. (i) The first is the establishment of a so-called ``cellular society,'' which is required to create a favorable microenvironment. (ii) The second is that GBM can be considered to be an organism, which fights to survive and develop. Since GBM evolves in a limited space, its only chance of development is to overcome the evolutionary checkpoints. For example, the deregulation of the normal Ca2+ signaling elements contributes to the progression of the disease. Thus, by manipulating the Ca2+ signaling, the GBM cells might not be killed, but might be reprogrammed toward a new fate that is either easy to cure or that has no aberrant functioning. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen