Biology subjects

Langevin, C.

Publications and source records attributed to Langevin, C..

4 recordsLinked to original sources

bioRxiv2026

Molecular characterization of thermo-adapted Novirhabdovirus variants and virulence in vivo in rainbow trout and zebrafish at different temperatures.

Controlling viral diseases in fish is a challenge for the sustainable development of aquaculture and improving the health of fish farms. Infectious hematopoietic necrosis virus (IHNV) is a major pathogen in aquaculture. It infects cold-water fish, but loses its infectivity at temperatures above 20{degrees}C. Since fish are poikilothermic animals, their body temperature fluctuates according to that of their environment. Faced with current climate change, it is crucial to understand how these pathogens will adapt to rising temperatures. Through a strategy simulating the impact of global warming, this virus has been progressively thermo-adapted to 25{degrees}C. The selected variant, IHNV25, replicates at 25{degrees}C while maintaining efficient replication at low temperatures, like its parental strain. Genome sequencing and a reverse genetics approach revealed that only 9 amino acid substitutions, distributed across 4 of the 6 viral genes, were essential for thermo-adaptation. Although IHNV25 was highly attenuated in its natural host, the rainbow trout, at any temperatures, it proved highly virulent when injected in zebrafish larvae at 20{degrees}C and 25{degrees}C, inducing severe symptoms identical to those observed in trout (hemorrhages, oedema, and exophthalmia). At both temperatures, mortality was preceded by a massive viral replication and a delayed and inefficient interferon and inflammatory response. Unlike the parental strain, IHNV25 was also capable of infecting larvae by bath immersion at 25{degrees}C, entering via the caudal fin, thus demonstrating its ability to cross the species barrier. The identification of viral markers of thermo-adaptation will therefore be of great interest for the epidemiological surveillance of field isolates.

microbiology↗

bioRxiv2024

Curcumin-mediated NRF2 induction limits inflammatory damage in preclinical models of cystic fibrosis

Overactive inflammation is directly correlated with airway damage and early death in individuals with cystic fibrosis (CF), a genetic disorder caused by mutation in the CFTR gene. Reducing the impact of inflammatory damage is therefore a major concern in CF. Several studies indicate that a decrease in the nuclear factor erythroid 2-related factor-2 (NRF2) signaling in people with CF may hamper their ability to alleviate oxidative stress and inflammation, although the role of NRF2 in CF inflammatory damage has not been determined. Therefore, we examined whether the phytochemical curcumin, an activator of NRF2, might provide a beneficial effect in the context of CF. Herein, combining Cftr-depleted zebrafish larvae as innovative biomedical model with CF patient-derived airway organoids (AOs), we sought to understand how NRF2 dysfunction leads to abnormal inflammatory status and impaired tissue remodeling, and determine the effects of curcumin in reducing inflammation and tissue damage in CF. We demonstrate that NFR2 is instrumental in efficiently regulating inflammatory and repair processes in vivo, thereby preventing acute neutrophilic inflammation and tissue damage. Importantly, curcumin treatment restores NRF2 activity in both CF zebrafish and AOs. Curcumin reduces neutrophilic inflammation in CF context, by rebalancing the production of epithelial ROS and pro-inflammatory cytokines. Furthermore, curcumin alleviates CF-associated tissue remodeling and allows tissue repair to occur. Our findings demonstrate that curcumin reduces inflammatory damage by restoring normal NRF2 activity, since disruption of Nrf2 pathway abrogated the effect of treatment in CF zebrafish. This work highlights the protective role of NRF2 in limiting inflammation and injury, and show that therapeutic strategies to normalize NRF2 activity using curcumin might simultaneously reduce inflammation and enhance tissue repair, and thus prevent infectious and inflammatory lung damage in CF.

immunology↗

bioRxiv2021

Endoglin deficiency elicits hypoxia-driven congestive heart failure in zebrafish.

Hereditary hemorrhagic Telangiectasia (HHT) is a rare genetic disease relying on mutations affecting components of Bone Morphogenetic Protein and Transforming Growth Factor-{beta} (BMP/TGF-{beta}) signaling pathway in endothelial cells. This disorder is characterized by arterio-venous malformations prone to rupture. and ensuing hemorrhages are responsible for iron deficiency anemia. Along with Activin receptor-like kinase ALK1, Endoglin is involved in the vast majority of HHT cases. In this report, we characterized zebrafish endoglin locus and demonstrated that it produces two phylogenetically conserved protein isoforms using a distinctive alternative splicing mechanism. Functional analysis of a Crispr/Cas9 zebrafish Endoglin mutant revealed that Endoglin deficiency results in massive death during the course from juvenile stage to adulthood. Endoglin deficient fish develop a cardiomegaly resulting in heart failure and hypochromic anemia which both stem from chronic hypoxia. Histological analysis and confocal imaging evidenced structural alterations of the developing gill and its underlying vascular network that tally with hypoxia. Finally, phenylhydrazine treatment demonstrated that lowering hematocrit/blood viscosity alleviates heart failure and enhances survival of Endoglin deficient fish. Altogether, our data indicate that Endoglin is crucial for gill vascular development and that further studies using zebrafish in general and this endoglin mutant in particular will provide crucial hints regarding the molecular and cellular events altered in HHT for the development of new therapeutic strategies. Summary StatementEndoglin deficiency in zebrafish recapitulates critical aspects of Hereditary Hemorrhagic Telangiectasia (HHT) and will thus constitute a valuable model in large scale screens for HHT-active drugs.

developmental biology↗

bioRxiv2021

Roscovitine exacerbates Mycobacterium abscessus infection by reducing NADPH oxidase-dependent neutrophil trafficking

Persistent neutrophilic inflammation associated with chronic pulmonary infection causes progressive lung injury and eventually death in individuals with cystic fibrosis (CF), a genetic disease caused by bi-allelic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We therefore examined whether Roscovitine, a cyclin-dependent kinase inhibitor that (in other conditions) reduces inflammation while promoting host defence, might provide a beneficial effect in the context of CF. Herein, using CFTR-depleted zebrafish larvae as an innovative vertebrate model of CF immuno-pathophysiology, combined with murine and human approaches, we sought to determine the effects of Roscovitine on innate immune responses to tissue injury and pathogens in CF condition. We show that Roscovitine exerts anti-inflammatory and pro-resolution effects in neutrophilic inflammation induced by infection or tail amputation in zebrafish. Roscovitine reduces overactive epithelial ROS-mediated neutrophil trafficking, by reducing DUOX2/NADPH-oxidase activity, and accelerates inflammation resolution by inducing neutrophil apoptosis and reverse migration. Importantly, while Roscovitine efficiently enhances intracellular bacterial killing of Mycobacterium abscessus in human CF macrophages ex vivo, we found that treatment with Roscovitine results in worse infection in mouse and zebrafish models. By interfering with DUOX2/NADPH oxidase-dependent ROS production, Roscovitine reduces the number of neutrophils at infection sites, and consequently compromises granuloma formation and maintenance, favouring extracellular multiplication of M. abscessus and more severe infection. Our findings bring important new understanding of the immune-targeted action of Roscovitine and have significant therapeutic implications for safety targeting inflammation in CF.

microbiology↗