Publications by authors named "Flavie Moreau"

11 Publications

  • Page 1 of 1

Pulmonary BCG induces lung-resident macrophage activation and confers long-term protection against tuberculosis.

Sci Immunol 2021 Sep 24;6(63):eabc2934. Epub 2021 Sep 24.

Grupo de Genética de Micobacterias, IIS Aragón, Facultad de Medicina, Universidad de Zaragoza, C/ Domingo Miral s/n, 50009 Zaragoza, Spain.

[Figure: see text].
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http://dx.doi.org/10.1126/sciimmunol.abc2934DOI Listing
September 2021

Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology.

PLoS Pathog 2021 Sep 13;17(9):e1009927. Epub 2021 Sep 13.

Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France.

Regulated cell necrosis supports immune and anti-infectious strategies of the body; however, dysregulation of these processes drives pathological organ damage. Pseudomonas aeruginosa expresses a phospholipase, ExoU that triggers pathological host cell necrosis through a poorly characterized pathway. Here, we investigated the molecular and cellular mechanisms of ExoU-mediated necrosis. We show that cellular peroxidised phospholipids enhance ExoU phospholipase activity, which drives necrosis of immune and non-immune cells. Conversely, both the endogenous lipid peroxidation regulator GPX4 and the pharmacological inhibition of lipid peroxidation delay ExoU-dependent cell necrosis and improve bacterial elimination in vitro and in vivo. Our findings also pertain to the ExoU-related phospholipase from the bacterial pathogen Burkholderia thailandensis, suggesting that exploitation of peroxidised phospholipids might be a conserved virulence mechanism among various microbial phospholipases. Overall, our results identify an original lipid peroxidation-based virulence mechanism as a strong contributor of microbial phospholipase-driven pathology.
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http://dx.doi.org/10.1371/journal.ppat.1009927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460005PMC
September 2021

Parallel in vivo experimental evolution reveals that increased stress resistance was key for the emergence of persistent tuberculosis bacilli.

Nat Microbiol 2021 08 22;6(8):1082-1093. Epub 2021 Jul 22.

Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France.

Pathogenomic evidence suggests that Mycobacterium tuberculosis (MTB) evolved from an environmental ancestor similar to Mycobacterium canettii, a rare human pathogen. Although the adaptations responsible for this transition are poorly characterized, the ability to persist in humans seems to be important. We set out to identify the adaptations contributing to the evolution of persistence in MTB. We performed an experimental evolution of eight M. canettii populations in mice; four populations were derived from the isolate STB-K (phylogenomically furthest from MTB) and four from STB-D (closest to MTB), which were monitored for 15 and 6 cycles, respectively. We selected M. canettii mutants with enhanced persistence in vivo compared with the parental strains, which were phenotypically closer to MTB. Genome sequencing of 140 mutants and complementation analysis revealed that mutations in two loci were responsible for enhanced persistence. Most of the tested mutants were more resistant than their parental strains to nitric oxide, an important effector of immunity. Modern MTB were similarly more resistant to nitric oxide than M. canettii. Our findings demonstrate phenotypic convergence during experimental evolution of M. canettii, which mirrors natural evolution of MTB. Furthermore, they indicate that the ability to withstand host-induced stresses was key for the emergence of persistent MTB.
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http://dx.doi.org/10.1038/s41564-021-00938-4DOI Listing
August 2021

Response letter to the Editor.

Semin Arthritis Rheum 2021 May 8. Epub 2021 May 8.

University of Maryland School of Medicine, Baltimore, MD, United States.

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http://dx.doi.org/10.1016/j.semarthrit.2021.05.001DOI Listing
May 2021

Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study.

Ann Rheum Dis 2021 May 7. Epub 2021 May 7.

Rheumatology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Objective: The FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) trial assessed efficacy and safety of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin in patients with knee osteoarthritis. Here, we report 5-year efficacy and safety results.

Methods: Patients were randomised to intra-articular sprifermin 100 µg or 30 µg every 6 months (q6mo) or 12 months, or placebo, for 18 months. The primary analysis was at year 2, with follow-up at years 3, 4 and 5. Additional post hoc exploratory analyses were conducted in patients with baseline minimum radiographic joint space width 1.5-3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain 40-90, a subgroup at risk (SAR) of progression.

Results: 378 (69%) patients completed the 5-year follow-up. A significant dose-response in total femorotibial joint cartilage thickness with sprifermin (trend test, p<0.001) and a 0.05 mm mean difference with sprifermin 100 µg q6mo versus placebo (95% CI 0.00 to 0.10; p=0.015) were sustained to year 5. WOMAC pain scores improved ~50% from baseline in all groups. No patient in the 100 µg q6mo group had replacement of the treated knee. 96%-98% of patients receiving sprifermin and 98% placebo reported adverse events, most were mild or moderate and deemed unrelated to treatment. Adverse event-related study withdrawals were <10%. Differentiation in WOMAC pain between sprifermin 100 µg q6mo and placebo in the SAR (n=161) at year 3 was maintained to year 5 (-10.08; 95% CI -25.68 to 5.53).

Conclusion: In the longest DMOAD trial reported to date, sprifermin maintained long-term structural modification of articular cartilage over 3.5 years post-treatment. Potential translation to clinical benefit was observed in the SAR.

Trial Registration Number: NCT01919164.
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http://dx.doi.org/10.1136/annrheumdis-2020-219181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292562PMC
May 2021

The effects of sprifermin on symptoms and structure in a subgroup at risk of progression in the FORWARD knee osteoarthritis trial.

Semin Arthritis Rheum 2021 04 11;51(2):450-456. Epub 2021 Mar 11.

Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and NIHR Leeds Biomedical Research Centre, Chapel Allerton Hospital, Leeds, UK. Electronic address:

Objective: To assess pain outcomes and cartilage thickness change in a subgroup at risk (SAR) of further progression in the FORWARD trial of knee osteoarthritis patients treated with sprifermin.

Methods: Patients were randomised 1:1:1:1:1 to: sprifermin 100 µg every 6 months (q6mo), 100 µg q12mo, 30 µg q6mo, 30 µg q12mo, or placebo for 18 months. SAR was defined as baseline medial or lateral minimum joint-space width (mJSW) 1.5-3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score 40-90 units. Follow-up to 3 years was included in the analysis. Treatment benefit was explored by repeated measures, linear dose-effect trends by timepoint.

Results: The SAR comprised 161 (29%) of 549 patients. Mean difference (95% CI) in WOMAC pain at year 3 for sprifermin 100 µg q6mo vs placebo SAR was -8.75 (-22.42, 4.92) for SAR vs 0.97 (-6.22, 8.16) for the intent-to-treat population. SAR placebo patients lost more cartilage over 2 years than the modified ITT (mITT) placebo arm (mean change from baseline, mm [SD]: -0.05 [0.10] vs -0.02 [0.07]). Net total femorotibial joint thickness gain with sprifermin 100 µg q6mo (adjusted mean difference from placebo [95% CI] was similar in the SAR and in the mITT group: 0.06 [0.01, 0.11] vs 0.05 [0.03, 0.07]).

Conclusions: Selection for low mJSW and moderate-to-high pain at baseline resulted in more rapid disease progression and demonstrated translation of structure modification (with maintained net benefit on total cartilage thickness) into symptomatic benefit. This subgroup may represent a target population for future trials.

Clinical Trial Registration: NCT01919164.
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http://dx.doi.org/10.1016/j.semarthrit.2021.03.005DOI Listing
April 2021

Efficacy of Bedaquiline, Alone or in Combination with Imipenem, against Mycobacterium abscessus in C3HeB/FeJ Mice.

Antimicrob Agents Chemother 2020 05 21;64(6). Epub 2020 May 21.

UVSQ, INSERM, Infection et Inflammation (U1173), Université Paris-Saclay, Montigny-le-Bretonneux, France.

lung infections remain difficult to treat. Recent studies have recognized the power of new combinations of antibiotics, such as bedaquiline and imipenem, although data have questioned this combination. We report that the efficacy of bedaquiline-imipenem combination treatment relies essentially on the activity of bedaquiline in a C3HeB/FeJ mice model of infection with a rough variant of The addition of imipenem contributed to clearing the infection in the spleen.
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http://dx.doi.org/10.1128/AAC.00114-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269509PMC
May 2020

Translational strategies in drug development for knee osteoarthritis.

Drug Discov Today 2020 06 3;25(6):1054-1064. Epub 2020 Apr 3.

EMD Serono Research and Development Institute, Billerica, MA, USA (A business of Merck, Darmstadt, Germany).

Osteoarthritis (OA) is a common disease worldwide with large unmet medical needs. To bring innovative treatments to OA patients, we at Merck have implemented a comprehensive strategy for drug candidate evaluation. We have a clear framework for decision-making in our preclinical pipeline, to design our clinical proof-of-concept trials for OA patients. We have qualified our strategy to define and refine dose and dosing regimen, for treatments administered either systemically or intra-articularly (IA). We do this through preclinical in vitro and in vivo studies, and by back-translating results from clinical studies in OA patients.
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http://dx.doi.org/10.1016/j.drudis.2020.03.015DOI Listing
June 2020

The Kuvan(®) Adult Maternal Paediatric European Registry (KAMPER) Multinational Observational Study: Baseline and 1-Year Data in Phenylketonuria Patients Responsive to Sapropterin.

JIMD Rep 2015 31;23:35-43. Epub 2015 Mar 31.

Department of Pediatrics, University of Heidelberg, Heidelberg, Germany,

Introduction: Sapropterin dihydrochloride (Kuvan(®)), a synthetic 6R-diastereoisomer of tetrahydrobiopterin (BH4), is approved in Europe for the treatment of patients aged ≥4 years with hyperphenylalaninaemia (HPA) due to BH4-responsive phenylalanine hydroxylase (PAH) deficiency, in conjunction with a phenylalanine-restricted diet, and also for the treatment of patients with BH4 deficiency.

Aims/methods: KAMPER is an ongoing, observational, multicentre registry with the primary objective of providing information over 15 years on long-term safety of sapropterin dihydrochloride treatment in patients with HPA. Here we report initial data on characteristics from patients recruited by the time of the third interim analysis and results at 1 year.

Results: Overall, 325 patients from 55 sites in seven European countries were included in the analysis: 296 (91.1%) patients with PAH deficiency (median [Q1, Q3] age, 10.3 [7.2, 15.0] years) and 29 (8.9%) with BH4 deficiency (12.8 [6.6, 18.9] years). Fifty-nine patients (18.2%) were aged ≥18 years; 4 patients were pregnant. No elderly patients (aged ≥65 years) or patients with renal or hepatic insufficiency were enroled in the study. Twelve-month data were available for 164 patients with PAH deficiency and 16 with BH4 deficiency. No new safety concerns were identified as of May 2013.

Conclusions: Initial data from KAMPER show that sapropterin dihydrochloride has a favourable safety profile. Registry data collected over time will provide insight into the management and outcomes of patients with PAH deficiency and BH4 deficiency, including long-term safety, impact on growth and neurocognitive outcomes and the effect of sapropterin dihydrochloride treatment on populations of special interest.
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http://dx.doi.org/10.1007/8904_2015_425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484899PMC
June 2015

Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator.

Proc Natl Acad Sci U S A 2014 Aug 21;111(31):11491-6. Epub 2014 Jul 21.

Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France;Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France;

Although the bovine tuberculosis (TB) agent, Mycobacterium bovis, may infect humans and cause disease, long-term epidemiological data indicate that humans represent a spill-over host in which infection with M. bovis is not self-maintaining. Indeed, human-to-human transmission of M. bovis strains and other members of the animal lineage of the tubercle bacilli is very rare. Here, we report on three mutations affecting the two-component virulence regulation system PhoP/PhoR (PhoPR) in M. bovis and in the closely linked Mycobacterium africanum lineage 6 (L6) that likely account for this discrepancy. Genetic transfer of these mutations into the human TB agent, Mycobacterium tuberculosis, resulted in down-regulation of the PhoP regulon, with loss of biologically active lipids, reduced secretion of the 6-kDa early antigenic target (ESAT-6), and lower virulence. Remarkably, the deleterious effects of the phoPR mutations were partly compensated by a deletion, specific to the animal-adapted and M. africanum L6 lineages, that restores ESAT-6 secretion by a PhoPR-independent mechanism. Similarly, we also observed that insertion of an IS6110 element upstream of the phoPR locus may completely revert the phoPR-bovis-associated fitness loss, which is the case for an exceptional M. bovis human outbreak strain from Spain. Our findings ultimately explain the long-term epidemiological data, suggesting that M. bovis and related phoPR-mutated strains pose a lower risk for progression to overt human TB, with major impact on the evolutionary history of TB.
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http://dx.doi.org/10.1073/pnas.1406693111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128152PMC
August 2014

Multiple deletions in the polyketide synthase gene repertoire of Mycobacterium tuberculosis reveal functional overlap of cell envelope lipids in host-pathogen interactions.

Cell Microbiol 2014 Feb 16;16(2):195-213. Epub 2013 Oct 16.

CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), BP 64182, 205 route de Narbonne, F-31077, Toulouse, France; UPS, IPBS, Université de Toulouse, F-31077, Toulouse, France.

Several specific lipids of the cell envelope are implicated in the pathogenesis of M. tuberculosis (Mtb), including phthiocerol dimycocerosates (DIM) that have clearly been identified as virulence factors. Others, such as trehalose-derived lipids, sulfolipids (SL), diacyltrehaloses (DAT) and polyacyltrehaloses (PAT), are believed to be essential for Mtb virulence, but the details of their role remain unclear. We therefore investigated the respective contribution of DIM, DAT/PAT and SL to tuberculosis by studying a collection of mutants, each with impaired production of one or several lipids. We confirmed that among those with a single lipid deficiency, only strains lacking DIM were affected in their replication in lungs and spleen of mice in comparison to the WT Mtb strain. We found also that the additional loss of DAT/PAT, and to a lesser extent of SL, increased the attenuated phenotype of the DIM-less mutant. Importantly, the loss of DAT/PAT and SL in a DIM-less background also affected Mtb growth in human monocyte-derived macrophages (hMDMs). Fluorescence microscopy revealed that mutants lacking DIM or DAT/PAT were localized in an acid compartment and that bafilomycin A1, an inhibitor of phagosome acidification, rescued the growth defect of these mutants. These findings provide evidence for DIM being dominant virulence factors that mask the functions of lipids of other families, notably DAT/PAT and to a lesser extent of SL, which we showed for the first time to contribute to Mtb virulence.
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http://dx.doi.org/10.1111/cmi.12214DOI Listing
February 2014
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