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Le modèle d'arthrite induite par adjuvant (AIA) mime les caractéristiques physiopathologiques de la polyarthrite rhumatoïde (PR), avec une forte prévalence et reproductibilité. Yes-associated protein (YAP) est un facteur de transcription mécano-sensible impliqué dans le développement de la PR, en favorisant le phénotype inflammatoire des fibroblast-like synoviocytes (FLS). Nos travaux antérieurs ont montré que CCL2 est sur-exprimé dans les chevilles AIA, ainsi que dans les FLS de PR en réponse à un stress mécanique. La décharge mécanique empêchant le développement de l'arthrite, nous avons émis l'hypothèse que les mécanismes impliqués dépendaient à la fois de YAP et de CCL2. L'objectif était donc de déterminer si l'inhibition de YAP et de CCL2 pouvait recréer la prévention de l'arthrite induite par la décharge mécanique dans le modèle AIA. L'arthrite a été induite chez des rats femelles (3–4 semaines), définissant le jour (J)0. Les rats AIA ont reçu différents traitements à partir de J6 : deux groupes avec de la vertéporfine (VP) pour inhiber l'activité transcriptionnelle de YAP jusqu'à J12 (groupe VP-J12) ou J16 (groupe VP-J16), un groupe avec un anticorps anti-CCL2 (α-CCL2), un groupe avec VP(J12)+α-CCL2, et un groupe contrôle (CTR). La circonférence de la cheville et le score d'arthrite ont été utilisés pour évaluer la sévérité de l'arthrite. À J17, les chevilles ont été prélevées pour analyser les paramètres osseux au μCT ainsi que l'expression génique. L'arthrite a débuté à partir de J10, sauf dans le groupe VP + α-CCL2 où l'apparition clinique a été observée à J11 (Figure 1A). Les groupes VP, α-CCL2 et VP+α-CCL2 ont développé une arthrite moins sévère par rapport au groupe CTR. L'évolution de la sévérité de l'arthrite était similaire entre les groupes VP et α-CCL2, alors que le groupe VP+α-CCL2 présentait le plus faible score d'arthrite par rapport à ces groupes, notamment par rapport au groupe VP (p < 0,01). De plus, la porosité corticale était nettement diminuée dans le groupe VP+α-CCL2 par rapport au groupe CTR (Figure 1B). L'expression de gènes inflammatoires (TNF, IL1B, IL17, CCL2) dans la cheville était similaire entre les groupes VP-J12 et CTR, contrairement aux gènes de résorption et de dégradation osseuse qui avaient tendance à être moins exprimés dans le groupe VP-J12 (RANKL, MMP13, CTSK, MMP9). Les groupes VP-J16, α-CCL2 et VP+α-CCL2 avaient une plus faible expression de l'ensemble de ces gènes comparé au groupe CTR, avec une expression similaire entre eux. Il en était de même pour l'expression des gènes cibles de YAP (CTGF et CYR61). Il y a une discordance ente l'évaluation clinique et de l'expression génique dans la cheville. Premièrement, le temps d'administration de la VP ne modifie pas l'inflammation clinique ni la perte osseuse, alors qu'une administration de VP jusqu'à J16 diminue l'expression de la majorité des gènes inflammatoires, de dégradation et de résorption osseuse comparé à un traitement jusqu'à J12. De plus, l'administration de VP+α-CCL2 avait un effet plus prononcé sur la diminution de la sévérité de l'arthrite ainsi que sur la prévention de la porosité corticale associée. En revanche, cet effet n'était pas retrouvé au niveau de l'expression génique dans la cheville, avec une expression similaire au groupe VP J16 ou α-CCL2. L'inhibition combinée de YAP et CCL2 a eu un effet additif sur la diminution de la sévérité de l'arthrite ainsi qu'un effet bénéfique sur la porosité corticale. Elle n'a cependant pas prévenu l'arthrite comme observé lors de la décharge mécanique, signifiant qu'un autre mécanisme est impliqué dans le développement de l'arthrite en réponse à un stress mécanique. [ABSTRACT FROM AUTHOR]

In this study, we investigated gene expression in vitro of human primary Aortic smooth muscle cells (AoSMCs) in response to 9% physiological dynamic stretch over a 4 to 72-h timeframe using RT-qPCR. AoSMC were derived from primary culture and were exposed to continuous cycles of stretch and relaxation at 1 Hz by a computer-controlled Flex Jr.™ Tension System. Unstretched control AoSMCs were simultaneously cultured in the same dishes. Our results revealed a rapid and significant upregulation of specific genes (COL1A1, FBN1, LAMA5, TGFBR1 and TGFBR2) within the initial 4 h for AoSMCs subjected to dynamic stretching, whilst control cells did not respond within the same 4 h. The upregulated genes were the ones associated with extracellular matrix (ECM) fibrillogenesis and regulation of traction forces. Interestingly, stretched cells maintained stable gene expression between 4 and 72 h, whilst control cells exhibited variations over time in the absence of mechanical cues. These findings shed light on the essential role played by pulsatile stretches in the regulation of gene expressions by AoSMCs and the intricate processes governing their mechanobiological function, paving the way for further investigations in cardiovascular health., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

We report two outbreaks of Lassa fever that occurred in Benin in 2014 and 2016 with 20 confirmed cases and 50% (10/20) mortality. Benin was not previously considered to be an endemic country for Lassa fever, resulting in a delay to diagnose the disease and its human transmission. Molecular investigations showed the viral genomes to be similar to that of the Togo strain, which is genetically very different from other known strains and confirms the existence of a new lineage. Endemic circulation of Lassa virus in a new territory and the genetic diversity thus confirm that this virus represents a growing threat for West African people. Given the divergence of the Benin strain from the prototypic Josiah Sierra Leone strain frequently used to generate vaccine candidates, the efficacy of vaccine candidates should also be demonstrated with this strain.

Background: In spite of recurrent and dramatic outbreaks, there are no therapeutics approved against Ebola virus disease. Favipiravir, a RNA polymerase inhibitor active against several RNA viruses, recently demonstrated significant but not complete protection in a non-human primate model of Ebola virus disease. In this study, we assessed the benefit of the combination of favipiravir and ribavirin, another broad spectrum antiviral agent, in the same model., Methods: 15 female cynomolgus macaques were challenged intramuscularly with 1,000 FFU of Ebola virus Gabon 2001 strain and followed for 21 days. All animals received favipiravir 180 mg/kg twice a day (BID), either as monotherapy (n = 5) or in combination with ribavirin (n = 10). Ribavirin was given either at the dose 10 mg/kg BID (n = 5) or 5 mg/kg BID (n = 5). Favipiravir and ribavirin were initiated two and one days before viral challenge respectively and treatment were continued for 14 days. Treatment effects on viral and hematological markers were assessed using a mathematical model. Survival rate of 0% and 20% were obtained in macaques receiving favipiravir plus ribavirin 10 and 5 mg/kg BID, respectively, compared to 40% in the favipiravir monotherapy group (P = 0.061 when comparing monotherapy and bitherapy, log rank). Viral dynamic modeling analysis did not identify an association between plasma concentrations of ribavirin and viral load levels. Using a model of erythropoiesis, plasma concentrations of ribavirin were strongly associated with a hemoglobin drop (p = 0.0015)., Conclusion: Ribavirin plus favipiravir did not extend survival rates and did not lower viral replication rate compared to favipiravir monotherapy in this animal model. Patients receiving this combination in other indications, such as Lassa fever, should be closely monitored to prevent potential toxicity associated with anemia., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: We have previously reported that human adenovirus (HAdV) reference strains clearly show species-dependent resistance to ribavirin, whereas different species of HAdV are equally sensitive to cidofovir. All the serotypes tested were susceptible to cidofovir, whereas only serotypes from species C were sensitive to ribavirin. Here, we aimed to extend these investigations to clinical isolates., Methods: In vitro, we tested 126 isolates obtained from 65 patients included in a European survey of HAdV infection., Results: Among the 126 isolates tested, all presented cidofovir 50% inhibitory concentration (IC50) in the same range as the HAdV 5 reference strain. Regarding ribavirin, all isolates from species C (79 tested) showed an IC50 comparable with previously reported results for reference strains; however, 24/32, 2/6 and 3/3 tested isolates from species A, B and D, respectively, were shown to have a ribavirin IC50 comparable with the HAdV 5 reference strain (species C), contrary to previous observations for reference strains of the same species. Among patients who were treated with cidofovir for disseminated HAdV infection, > or = 4 sequential isolates could be obtained from 9 patients; no variation in cidofovir susceptibility could be detected., Conclusions: Cidofovir is active in vitro in all HAdV clinical isolates. Ribavirin was revealed to be active on most HAdV isolates from species A, B and D, and in all isolates from species C. Finally, no resistance to cidofovir became apparent in sequential isolates obtained from treated patients.

Adenovirus infections are a frequent and serious complication following allogeneic haematopoietic stem cell transplantation (HSCT). The antiviral drugs cidofovir and ribavirin have been used as first-line therapy for disseminated infections with variable results. In the present study, in vitro susceptibility to these two drugs was evaluated on HEp-2 cells in adenovirus reference strains representing serotypes of each of the six species and in clinical isolates. Susceptibility to cidofovir was comparable between species with inhibition of replication of all tested serotypes in a narrow dose range (IC50=17-81 microM). However, susceptibility to ribavirin was highly dependent on the species. Serotypes from species A, B, D, E and F were all resistant to ribavirin (IC50=396 to >500 microM). Only replication of serotypes from species C was inhibited by ribavirin (IC50=48-108 microM). This species-dependent susceptibility of adenovirus to ribavirin was confirmed in clinical isolates. When tested on other cell lines (PLC, A549 and 293), all species were revealed to be resistant to ribavirin. If our in vitro findings are predictive of virological responses in vivo, these results suggest that ribavirin would not be effective for management of non-C species adenovirus infections after HSCT.