Resistance of Omicron subvariants BA.2.75.2, BA.4.6 and BQ.1.1 to neutralizing antibodies

Convergent evolution of SARS-CoV-2 Omicron BA.2, BA.4 and BA.5 lineages has led to the emergence of several new subvariants, including BA.2.75.2, BA.4.6. and BQ.1.1. The subvariants BA.2.75.2 and BQ.1.1 are expected to become predominant in many countries in November 2022. They carry an additional and often redundant set of mutations in the spike, likely responsible for increased transmissibility and immune evasion. Here, we established a viral amplification procedure to easily isolate Omicron strains. We examined their sensitivity to 6 therapeutic monoclonal antibodies (mAbs) and to 72 sera from Pfizer BNT162b2-vaccinated individuals, with or without BA.1/BA.2 or BA.5 breakthrough infection. Ronapreve (Casirivimab and Imdevimab) and Evusheld (Cilgavimab and Tixagevimab) lost any antiviral efficacy against BA.2.75.2 and BQ.1.1, whereas Xevudy (Sotrovimab) remained weakly active. BQ.1.1 was also resistant to Bebtelovimab. Neutralizing titers in triply vaccinated individuals were low to undetectable against BQ.1.1 and BA.2.75.2, 4 months after boosting. A BA.1/BA.2 breakthrough infection increased these titers, which remained about 18-fold lower against BA.2.75.2 and BQ.1.1, than against BA.1. Reciprocally, a BA.5 breakthrough infection increased more efficiently neutralization against BA.5 and BQ.1.1 than against BA.2.75.2. Thus, the evolution trajectory of novel Omicron subvariants facilitated their spread in immunized populations and raises concerns about the efficacy of most currently available mAbs.N

COUP-TFII Controls Mouse Pancreatic β-Cell Mass through GLP-1-β-Catenin Signaling Pathways

Background: The control of the functional pancreatic beta-cell mass serves the key homeostatic function of releasing the right amount of insulin to keep blood sugar in the normal range. It is not fully understood though how beta-cell mass is determined

COUP-TFII : sa régulation et son rôle dans le contrôle du métabolisme glucido-lipidique chez le souriceau nouveau-né

Metabolic adaptation to nutritional changes that occurs at birth is essential for newborn mammal survival. This is particularly crucial for newborn mice in which glucose availability from milk is low. Numerous signalling pathways and transcription factors are involved in these postnatal adaptations. The work presented in this thesis shows that nuclear receptor COUP-TFII (Chicken Ovalbumin Upstream Promoter, Transcription Factor II) plays a central role in this nutritional adaptation. Indeed, its hepatic gene expression increases during the rst days after birth. Two factors are involved in this postnatal increase : glucagon and nuclear receptor PPAR that directly controls COUP-TFII gene expression secondarily to its binding to DNA consensus responsive element (DR-1). To study COUP-TFII function, two strategies (shRNA mediating invalidation and functional invalidation using a dominant negative COUP-TFII protein) were used in 4 day-old suckling mice. Hepatic invalidation of COUP-TFII induces a marked hypoglycaemia and hypoketonemia. At this developmental stage, hepatic glucose production is ensured by gluconeogenesis that is energetically dependant of fatty acid oxidation that provide cofactors (NADH, H+ and acetyl-CoA) required for speci c gluconeogenic enzymes activities. Using the crossover plot technique, we showed that pyruvate carboxylase (acetyl-CoA dependant) and glycerad ehyde-3- phosphate dehydrogenase (NADH, H+ dependant) are involved in the inhibition of hepatic gluconeogenesis in COUP-TFII invalidated mice.Moreover, hepatic COUP-TFII invalidation reduces key gluconeogenic (PEPCK, glucose-6-phosphatase) and fatty acid oxidation (CPT-1, mHMG-CoA synthase, FABP-1) gene expression. The hypoglycaemic and hypoketonemic phenotype is reversed by pharmacologic activation of PPAR (a major factor in the regulation of fatty acid oxidation gene expression) suggesting that inhibition of gluconeogenesis is mainly due to the reduction of fatty acid oxidation. All together, these data provide evidences that COUP-TFII is a major actor in the regulation of hepatic glucose and lipid metabolisms in newborn mice.L'adaptation m etabolique aux changements nutritionnels qui surviennent a la naissance est cruciale pour la survie des mammif eres nouveau-n es. C'est particuli erement important chez la souris nouveau-n e en raison d'un apport lact e en glucides tr es r eduit. De nombreuses voies de signalisation et facteurs de transcription permettent l'adaptation postnatale du m etabolisme a ce r egime, Le travail pr esent e dans cette th ese montre que le r ecepteur nucl eaire COUP-TFII (Chicken Ovalbumin Upstream Promoter, Transcription Factor II) joue un r^ole capital dans cette adaptation nutritionnelle. Ainsi, son expression h epatique augmente d es la naissance. Deux facteurs sont impliqu es dans cette augmentation : le glucagon et le r ecepteur nucl eaire PPAR qui contr^ole directement l'expression de COUP-TFII en se liant a son promoteur via un el ement consensus de type DR-1. Pour etudier la fonction de COUP-TFII, deux techniques d'invalidation ad enovirale (invalidation g enique par ARN interf erence et invalidation fonctionnelle utilisant une prot eine dominante n egative), ont et e utilis ees chez le souriceau de 4 jours. L'invalidation h epatique de COUP-TFII provoque une hypoglyc emie et une hypoc eton emie. A ce stade de d eveloppement, la production h epatique de glucose est asur ee par la n eoglucogen ese qui est energ etiquement d ependante de l'oxydation des acides gras qui fournit des coenzymes r eduits (NADH, H+) et de l'ac etyl-CoA n ecessaires au fonctionnement de certaines enzymes de la n eoglucogen ese. En utilisant la technique du crossover plot, nous avons montr e que deux etapes enzymatiques de la n eoglucog en ese sont inhib ees dans le foie des souris invalid ees pour COUP-TFII : la pyruvate carboxylase (d ependante de l'ac etyl-CoA) et la glyc erad ehyde-3-phosphate deshydrog enase (d ependante du NADH, H+). Ces e ets m etaboliques s'accompagnent de diminutions de l'expression de g enes cl es de la n eoglucog en ese (PEPCK, glucose-6-phosphatase) et de la -oxydation mitochondriale des acides gras (CPT-1, mHMG-CoA synthase, FABP-1). Le ph enotype hypoglyc emique et hypoc eton emique est normalis e par une activation pharmacologique de PPAR (un r egulateur majeur des g enes de l'oxydation des acides gras) sugg erant que l'inhibition de la n eoglucogen ese est la principalement la cons equence d'une diminution de l'oxydation des acides gras. Ces travaux font de COUP-TFIII un coordinateur majeur du m etabolisme h epatique postnatal chez la souris

COUP-TFII (sa régulation et son rôle dans le contrôle du métabolisme glucido-lipidique chez le souriceau nouveau-né)

L adaptation aux changements nutritionnels qui surviennent à la naissance est cruciale pour la survie des mammifères nouveau-nés. C est particulièrement important chez la souris en raison d un apport lacté en glucides réduit. De nombreuses voies de signalisation et facteurs de transcription permettent l'adaptation postnatale du métabolisme. Le travail présenté montre que le récepteur nucléaire COUP-TFII joue un rôle capital dans cette adaptation nutritionnelle. Son expression hépatique augmente dès la naissance et implique deux facteurs : le glucagon et PPARa qui contrôle directement l'expression de COUP-TFII. Pour étudier la fonction de COUP-TFII, deux techniques d'invalidation adénovirale (génique par ARN interférence et fonctionnelle utilisant une protéine dominante négative) ont été utilisées chez le souriceau de 4 jours. L'invalidation hépatique de COUP-TFII provoque une hypoglycémie et une hypocétonémie. La production hépatique de glucose est assurée par la néoglucogenèse qui est énergétiquement dépendante de l'oxydation des acides gras fournissant coenzymes réduits (NADH, H+) et acétyl-CoA nécessaires au fonctionnement de certaines enzymes de la néoglucogenèse. Deux étapes de la néoglucogénèse sont inhibées dans le foie des souris invalidées pour COUP-TFII : la pyruvate carboxylase (acétyl-CoA dépendante) et la glycéradéhyde-3-phosphate deshydrogénase (NADH, H+ dépendante). Ces effets métaboliques s'accompagnent de diminutions de l'expression de gènes de la néoglucogénèse (PEPCK, G-6-Pase) et de la ß-oxydation mitochondriale des acides gras (CPT-1, mHMG-CoA synthase, FABP-1). Ces travaux font de COUP-TFIII un coordinateur majeur du métabolisme hépatique postnatal.Adaptation to nutritional changes around birth are essential for mammals survival. This is particularly important for mice in which glucose availability in milk is low. Numerous signalling pathways and transcription factors are involved in postnatal adaptation of metabolism. This work shows that COUP-TFII plays a central role in this nutritional adaptation. Its hepatic expression increases after birth and is under control of two factors : glucagon and PPARa which directly controls COUP-TFII expression. To study COUP-TFII function, two adenoviral invalidation strategies (genic using a shRNA and functional using a dominant negative protein) were used in 4 days old mice. Hepatic invalidation of COUP-TFII induces hypoglycemia and hypoketonemia. Hepatic glucose production is ensured by gluconeogenesis that is enegetically dependant of fatty acid oxidation that provides cofactors (NADH, H+) and acetyl-CoA required for specific gluconeogenic enzymes. Two steps of gluconeogenesis are inhibited in the liver of COUP-TFII invalidated mice : pyruvate carboxylase (acetyl-CoA dependant) and glyceraldehyde-3-phosphate deshydrogenase (NADH, H+ dependant). Along with these metabolic effects, expression of several gluconeogenic genes (PEPCK, G-6-Pase) and beta oxidation genes (CPT-1, mHMG-CoA synthase, FABP-1) is decreased. This work provides evidence that COUP-TFII is a major actor in the regulation of hepatic glucose and lipid metabolisms in newborn mice.PARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease

International audienceThe gut microbiota is a crucial actor in human physiology. Many of these effects are mediated by metabolites that are either produced by the microbes or derived from the transformation of environmental or host molecules. Among the array of metabolites at the interface between these microorganisms and the host is the essential aromatic amino acid tryptophan (Trp). In the gut, the three major Trp metabolism pathways leading to serotonin (5-hydroxytryptamine), kynurenine (Kyn), and indole derivatives are under the direct or indirect control of the microbiota. In this review, we gather the most recent advances concerning the central role of Trp metabolism in microbiota-host crosstalk in health and disease. Deciphering the complex equilibrium between these pathways will facilitate a better understanding of the pathogenesis of human diseases and open therapeutic opportunities

Hypothalamic ventromedial COUP-TFII protects against hypoglycemia-associated autonomic failure

The nuclear receptor Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) is an important coordinator of glucose homeostasis through its function in different organs such as the endocrine pancreas, adipose tissue, skeletal muscle, and liver. Recently we have demonstrated that COUP-TFII expression in the hypothalamus is restricted to a subpopulation of neurons expressing the steroidogenic factor 1 transcription factor, known to play a crucial role in glucose homeostasis. To understand the functional significance of COUP-TFII expression in the steroidogenic factor 1 neurons, we generated hypothalamic ventromedial nucleus-specific COUP-TFII KO mice using the cyclization recombination/locus of X-overP1 technology. The heterozygous mutant mice display insulin hypersensitivity and a leaner phenotype associated with increased energy expenditure and similar food intake. These mutant mice also present a defective counterregulation to hypoglycemia with altered glucagon secretion. Moreover, the mutant mice are more likely to develop hypoglycemia-associated autonomic failure in response to recurrent hypoglycemic or glucopenic events. Therefore, COUP-TFII expression levels in the ventromedial nucleus are keys in the ability to resist the onset of hypoglycemia-associated autonomic failure

Renal biopsy in very elderly patients (over 80 years): clinical presentation, histological diagnosis, and long-term outcome

International audiencePurpose: Data regarding the long-term outcome of very elderly (VE) patients undergoing renal biopsy (RB) are lacking. The objective of this study was to analyse the outcome of VE patients undergoing RB.Methods: All patients over 65 years that underwent native RB between 2004 and 2016 in our center were included. Among the 206 included patients, those over 80 years (VE, 46 patients) were analysed and compared to those aged 65-80 years (160 patients). The outcomes of the VE group were analysed.Results: Baseline characteristics, renal presentation, safety of RB and RB-related diagnosis were not different between VE patients and 65-80-year-old patients. Survival of VE patients was 73.1, 50.6 and 21.8% at 2, 4 and 6 years after RB, significantly poorer than those of 65-80-year-old group. Early death (< 1 year) occurred in 10 VE patients, was associated with a higher proteinuria-to-creatininuria ratio and tended to be associated with a more frequent dialysis need at RB. Of the 46 VE patients, 31 (67.4%) were diagnosed with a potentially reversible kidney disease, of whom 17 (40%) were started on immunosuppressive regimens. Survival of patients with a reversible kidney disease tended to be better than those with other diseases.Conclusion: RB appears as a safe and valuable procedure to assess diagnosis of kidney disease in VE patients. Our data suggest that RB is critical for the identification and treatment decision of patients with potentially reversible diseases and may translate in clinical improvement

EMissions d'Ammoniac et de gaz à effet de serre des FUMiers bovin (EMAFUM)

EMissions d'Ammoniac et de gaz à effet de serre des FUMiers bovin (EMAFUM

The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism

Abstract Cancer cells integrate multiple biosynthetic demands to drive unrestricted proliferation. How these cellular processes crosstalk to fuel cancer cell growth is still not fully understood. Here, we uncover the mechanisms by which the transcription factor Carbohydrate responsive element binding protein (ChREBP) functions as an oncogene during hepatocellular carcinoma (HCC) development. Mechanistically, ChREBP triggers the expression of the PI3K regulatory subunit p85α, to sustain the activity of the pro-oncogenic PI3K/AKT signaling pathway in HCC. In parallel, increased ChREBP activity reroutes glucose and glutamine metabolic fluxes into fatty acid and nucleic acid synthesis to support PI3K/AKT-mediated HCC growth. Thus, HCC cells have a ChREBP-driven circuitry that ensures balanced coordination between PI3K/AKT signaling and appropriate cell anabolism to support HCC development. Finally, pharmacological inhibition of ChREBP by SBI-993 significantly suppresses in vivo HCC tumor growth. Overall, we show that targeting ChREBP with specific inhibitors provides an attractive therapeutic window for HCC treatment

Antibiotic treatment using amoxicillin-clavulanic acid impairs gut mycobiota development through modification of the bacterial ecosystem

Background Effects of antibiotics on gut bacteria have been widely studied, but very little is known about the consequences of such treatments on the fungal microbiota (mycobiota). It is commonly believed that fungal load increases in the gastrointestinal tract following antibiotic treatment, but better characterization is clearly needed of how antibiotics directly or indirectly affect the mycobiota and thus the entire microbiota.Design We used samples from humans (infant cohort) and mice (conventional and human microbiota-associated mice) to study the consequences of antibiotic treatment (amoxicillin-clavulanic acid) on the intestinal microbiota. Bacterial and fungal communities were subjected to qPCR or 16S and ITS2 amplicon-based sequencing for micro biota analysis. In vitro assays further characterized bacterial-fungal interactions, with mixed cultures between specific bacteria and fungi.Results Amoxicillin-clavulanic acid treatment triggered a decrease in the total fungal population in mouse feces, while other antibiotics had opposite effects on the fungal load. This decrease is accompanied by a total remodelling of the fungal population with the enrichment in Aspergillus, Cladosporium, and Valsa genera. In the presence of amoxicillin-clavulanic acid, microbiota analysis showed a remodeling of bacterial microbiota with an increase in specific bacteria belonging to the Enterobacteriaceae. Using in vitro assays, we isolated different Enterobacteriaceae species and explored their effect on different fungal strains. We showed that Enterobacter hormaechei was able to reduce the fungal population in vitro and in vivo through yet unknown mechanisms.Conclusions Bacteria and fungi have strong interactions within the microbiota; hence, the perturbation initiated by an antibiotic treatment targeting the bacterial community can have complex consequences and can induce opposite alterations of the mycobiota. Interestingly, amoxicillin-clavulanic acid treatment has a deleterious effect on the fungal community, which may have been partially due to the overgrowth of specific bacterial strains with inhibiting or competing effects on fungi. This study provides new insights into the interactions between fungi and bacteria of the intestinal microbiota and might offer new strategies to modulate gut microbiota equilibrium.Peer reviewe