HAL-Pasteur
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Autoinflammatory encephalopathy due to PTPN1 haploinsufficiency: a case series
No full textInternational audienceBackgroundThrough the agnostic screening of patients with uncharacterised disease phenotypes for an upregulation of type I interferon (IFN) signalling, we identified a cohort of individuals heterozygous for mutations in PTPN1, encoding the protein-tyrosine phosphatase 1B (PTP1B). We aimed to describe the clinical phenotype and molecular and cellular pathology of this new disease.MethodsIn this case series, we identified patients and collected clinical and neuroradiological data through collaboration with paediatric neurology and clinical genetics colleagues across Europe (Czechia, France, Germany, Italy, Slovenia, and the UK) and Israel. Variants in PTPN1 were identified by exome and directed Sanger sequencing. The expression of IFN-stimulated genes was determined by quantitative (q) PCR or NanoString technology. Experiments to assess RNA and protein expression and to investigate type 1 IFN signalling were undertaken in patient fibroblasts, hTERT-immortalised BJ-5ta fibroblasts, and RPE-1 cells using CRISPR–Cas9 editing and standard cell biology techniques.FindingsBetween Dec 20, 2013, and Jan 11, 2023, we identified 12 patients from 11 families who were heterozygous for mutations in PTPN1. We found ten novel or very rare variants in PTPN1 (frequency on gnomAD version 4.1.0 of –6). Six variants were predicted as STOP mutations, two involved canonical splice-site nucleotides, and two were missense substitutions. In three patients, the variant occurred de novo, whereas in nine affected individuals, the variant was inherited from an asymptomatic parent. The clinical phenotype was characterised by the subacute onset (age range 1–8 years) of loss of motor and language skills in the absence of seizures after initially normal development, leading to spastic dystonia and bulbar involvement. Neuroimaging variably demonstrated cerebral atrophy (sometimes unilateral initially) or high T2 white matter signal. Neopterin in CSF was elevated in all ten patients who were tested, and all probands demonstrated an upregulation of IFN-stimulated genes in whole blood. Although clinical stabilisation and neuroradiological improvement was seen in both treated and untreated patients, in six of eight treated patients, high-dose corticosteroids were judged clinically to result in an improvement in neurological status. Of the four asymptomatic parents tested, IFN signalling in blood was normal (three patients) or minimally elevated (one patient). Analysis of patient blood and fibroblasts showed that tested PTPN1 variants led to reduced levels of PTPN1 mRNA and PTP1B protein, and in-vitro assays demonstrated that loss of PTP1B function was associated with impaired negative regulation of type 1 IFN signalling.InterpretationPTPN1 haploinsufficiency causes a type 1 IFN-driven autoinflammatory encephalopathy. Notably, some patients demonstrated stabilisation, and even recovery, of neurological function in the absence of treatment, whereas in others, the disease appeared to be responsive to immune suppression. Prospective studies are needed to investigate the safety and efficacy of specific immune suppression approaches in this disease population
Rough is salient: a conserved vocal niche to hijack the brain's salience system
No full textThe propensity to communicate extreme emotional states and arousal through salient, non-referential vocalizations is ubiquitous among mammals and beyond. Screams, whether intended to warn conspecifics or deter aggressors, require a rapid increase of air influx through vocal folds to induce nonlinear distortions of the signal. These distortions contain salient, temporally patterned acoustic features in a restricted range of the audible spectrum. These features may have a biological significance, triggering fast behavioural responses in the receivers. We present converging neurophysiological and behavioural evidence from humans and animals supporting that the properties emerging from non-linear vocal phenomena are ideally adapted to induce efficient sensory, emotional, and behavioural responses. We argue that these fast temporal -rough-modulations are unlikely to be an epiphenomenon of vocal production but rather the result of selective evolutionary pressure on vocal warning signals to promote efficient communication. In this view, rough features may have been selected and conserved as an acoustic trait to recruit ancestral sensory salience pathways and elicit optimal reactions in the receiver. By exploring the impact of rough vocalizations at the receiver's end, we review the perceptual, behavioural, and neural factors that may have shaped these signals to evolve as powerful communication tools
Les effets du changement climatique sur l’émergence de la dengue
No full textInternational audienceIn recent decades, dengue has become a global issue due to its rapid spread and significant public health impact. Climate change is recognized as a key factor in the geographical spread of dengue and its vectors. Climate change affects dengue transmission through changes in temperature and precipitation, which affect both vectors and arboviruses. Climate change can also disrupt human migration patterns facilitating the spread of the virus and the invasion of vectors into new regions. Understanding the impact of climate change on dengue and its vectors is essential for developing strategies to prevent and control the disease. Appropriate mosquito control strategies, enhanced epidemiological surveillance and tailored public health systems are needed to mitigate the increasing burden of dengue in the context of climate change.La dengue est une infection virale dont l’agent causal, le virus de la dengue (DENV), est transmis par les moustiques du genre Aedes. Au cours des dernières décennies, la dengue est devenue une préoccupation majeure en raison de sa propagation rapide et de son impact significatif sur la santé publique. Le changement climatique est reconnu comme un facteur majeur de l’expansion géographique de la dengue et de ses vecteurs. Le changement climatique influence la transmission de la dengue via des changements de température et de pluviosité affectant les moustiques vecteurs et l’arbovirus. Le changement climatique peut également perturber les migrations humaines, qui facilitent alors la dispersion du virus, et favoriser l’expansion de moustiques vecteurs vers de nouvelles régions. Il est essentiel de comprendre l’impact du changement climatique sur la dengue et ses vecteurs pour élaborer des stratégies efficaces de prévention et de contrôle de la maladie. Des stratégies adaptées de lutte contre les moustiques, une surveillance épidémiologique renforcée et un système de santé publique plus adaptée sont nécessaires pour atténuer le fardeau croissant de la dengue dans un contexte de changement climatique
Enhanced identification of Morganella spp. using MALDI-TOF mass spectrometry
No full textInternational audienceIntroduction: The genus Morganella, including clinically isolated species M. sibonii and M. morganii, has a still underexplored role in clinical microbiology. Despite the clinical relevance of Morganella spp., current MALDI-TOF commercial systems fail to differentiate these species. Whole genome sequencing (WGS) remains the most effective method to distinguish species. However, this method is not adapted for routine lab workflow. Enhancing MALDI-TOF’s accuracy could make it a rapid and effective approach for distinguishing Morganella species in routine laboratory diagnostics.Objectives: This study aims to improve the performance of MALDI-TOF for identifying Morganella spp. using WGS as the gold-standard reference method.Methods: We applied Machine Learning (ML) algorithms to a collection of 235 clinicial Morganella spp. strains to develop an optimized identification model. Whole genome sequencing was used to characterize these strains and perform phylogenetic analysis, categorizing 209 strains as M. morganii and 26 as M. sibonii.Results: The ML-based classifiers showed improved identification accuracy (44 of the 160 designed with accuracy at 1). Also, MS analysis identified 11 peaks able to discriminate between M. morganii and M. sibonii.Conclusion: Through development of a publicly-available online ML-based classifier, this study has improved the capacity of MALDI-TOF for distinguishing Morganella spp., providing a reliable, user-friendly solution suited to routine clinical diagnostics and supporting a better understanding of the roles of M. morganii and M. sibonii in human pathology
Provision of Preferred Nutrients to Macrophages Enables Salmonella to Replicate Intracellularly Without Relying on Type III Secretion Systems
No full textIntracellular survival and replication within macrophages are key virulence determinants of Salmonella enterica serovar Typhimurium. This phenomenon is traditionally attributed to the activity of its two Type III Secretion Systems (T3SS) and their associated effectors. A critical challenge for these bacteria is acquiring nutrients from inside the host cell. Thus, they modulate the metabolism of host cells to replicate. Given the metabolic plasticity of macrophages, a key unresolved question is how their metabolic heterogeneity shapes intracellular Salmonella replication. By using human primary macrophages and live-cell imaging to monitor bacterial dynamics at the single-cell level, we revealed that Salmonella does not replicate in all infected cells. However, supplementation with specific carbon sources used by Salmonella during infection accelerated bacterial replication and increased the proportion of macrophages showing replicative bacteria. Remarkably, this occurred even in the absence of functional T3SSs, as a Δ prgH /Δ ssaV double mutant was able to replicate in a subset of infected cells under favorable nutrient conditions. These phenotypes are further amplified in macrophages with higher glycolytic activity, such as the murine RAW 264.7 cell line. Further analyses demonstrated that enhanced Salmonella replication is not strictly dependent on host glycolytic activity but is instead driven by the ability of the host cell to take up the nutrients Salmonella prefers for its replication early during infection. In summary, our findings suggest that the dependence of Salmonella on its T3SSs for intracellular replication can be bypassed when host cells provide optimal access to key nutrients and highlight the impact of metabolic heterogeneity in shaping intracellular bacterial replication during infection of macrophages
Hicberg: Reconstruction of contact signals from repeated elements
No full textIn the course of their evolution, genomes can acquire various repeated elements, such as transposons, ribosomal DNA, duplicated genes or tandem repeats. These types of sequences cannot be processed directly by current high-throughput sequencing pipelines, as they generate short reads that cannot be unambiguously localized on reference genomes. We propose an algorithm called Hicberg that uses statistical inference with the computation of probability distributions to precisely reassign the positions of reads from repeated sequences in different paired omics data, such as Hi-C, Mnase-seq or ChIP-seq data. We show that Hicberg can generate new insights into the impact of repeated elements on the spatial organisation of genomes
The effect of school-based interventions on HPV vaccine-related knowledge, attitudes, and practices among adolescents in France: Secondary results from the PrevHPV trial
No full textInternational audienceBackground: In France, HPV vaccine uptake among adolescents remains a public health concern. Therefore, we examined changes in French adolescents' knowledge, attitudes, and practices (KAP) following exposure to HPV-vaccination-related interventions.Methods: Our cluster-randomized trial applied an incomplete factorial design to allocate three intervention components (in-school education, free in-school vaccination, and general practitioner [GP] trainings) into six arms, randomly assigned to 91 French municipalities. Adolescents' (N = 2758; typically aged 13-14) self-reported HPV-vaccine-related KAP was assessed via online questionnaires at baseline and follow-up. Using logistic regression, we estimated the decomposed effects of each intervention component on favorable responses to individual KAP items. Each model adjusted for the baseline level of the outcome. We conducted subgroup analyses of the effect of the education component.Results: Adolescents who received in-school education, compared to those who did not, provided improved responses on all knowledge items at follow-up. They also reported more favorable attitudes, which included the perceived benefit-risk balance (OR = 1.6 [95 %-CI, 1.2-2.0]) and judging reduced onward transmission as important (1.5 [1.1-2.1]). In-school education increased the likelihood of having HPV-vaccine-related discussions with friends (1.8 [1.2-2.6]). In-school vaccination increased adolescents' likelihood of knowing that friends are vaccinated (3.1 [2.2-4.2]), and perceived accessibility (2.2 [1.5-3.2]). Perceived difficulties in accessing clear vaccine information increased specifically among multilingual adolescents (0.5 [0.2-0.9]).Conclusion: Free in-school HPV vaccination significantly increases perceived ease of access to HPV vaccination for students who are already motivated to get vaccinated, and in-school education and motivation improves students' HPV vaccine-related knowledge and attitudes and can encourage them to get vaccinated. Thus, when offered together over the course of multiple academic years, we would expect to see increased vaccine uptake as adolescents become both more amenable toward vaccination and perceive easier access. Educational material needs tailoring for families from different linguistic and cultural backgrounds
Accurate genotyping of three major respiratory bacterial pathogens with ONT R10.4.1 long-read sequencing
No full textInternational audienceHigh-throughput massive parallel sequencing has significantly improved bacterial pathogen genomics, diagnostics, and epidemiology. Despite its high accuracy, short-read sequencing struggles with complete genome reconstruction and assembly of extrachromosomal elements such as plasmids. Long-read sequencing with Oxford Nanopore Technologies (ONT) presents an alternative that offers benefits including real-time sequencing and cost-efficiency, particularly useful in resource-limited settings. However, the historically higher error rates of ONT data have so far limited its application in high-precision genomic typing. The recent release of ONT's R10.4.1 chemistry, with significantly improved raw read accuracy (Q20+), offers a potential solution to this problem. The aim of this study was to evaluate the performance of ONT's latest chemistry for bacterial genomic typing against the gold standard Illumina technology, focusing on three respiratory pathogens of public health importance, Klebsiella pneumoniae , Bordetella pertussis , and Corynebacterium diphtheriae , and their related species. Using the Rapid Barcoding Kit V14, we generated and analyzed genome assemblies with different basecalling models, at different simulated depths of coverage. ONT assemblies were compared to the Illumina reference for completeness and core genome multilocus sequence typing (cgMLST) accuracy (number of allelic mismatches). Our results show that genomes obtained from raw ONT data basecalled with Dorado SUP v0.9.0, assembled with Flye, and with a minimum coverage depth of 35×, optimized accuracy for all bacterial species tested. Error rates were consistently below 0.5% for each cgMLST scheme, indicating that ONT R10.4.1 data is suitable for high-resolution genomic typing applied to outbreak investigations and public health surveillance
Duration of systemic antifungal therapy for patients with invasive fungal diseases: A reassessment
No full textInternational audienceInvasive fungal diseases are associated with significant morbidity and mortality, especially among immunocompromised patients, and often prompt for rapid and aggressive treatment aiming cure. Due to the expanding magnitude of patients burdened by chronic immunosuppression and affected by fungal diseases, the diversity of clinical settings has risen. This often results in prolonged therapy (induction, consolidation and maintenance) associated with potentially severe side effects, and clinicians face the challenging decisions of when and how to stop anti-fungal therapy. Adequate duration of therapy is poorly defined, hampered by the lack of dedicated trials to the question, the heterogeneity of cases (type of fungal pathogen, localization of infection, underlying host conditions) and various confounding factors that may influence the clinical response (e.g. persistence vs recovery of immunosuppression, impact of surgery). In this review, we aim to evaluate the existing data underlying the guidelines and recommendations of treatment duration for the most frequent invasive fungal diseases (cryptococcal meningitis, Pneumocystis pneumonia, invasive aspergillosis, invasive candidiasis and mucormycosis), as well as specific localizations of deep-seated diseases (osteo-articular or central nervous system diseases and endocarditis) and emerging considerations and strategies
Comparison of disc diffusion and Sensititre® Broth Microdilution methods for antimicrobial susceptibility testing of Bacteroides fragilis group clinical isolates following the French guidelines
No full textInternational audienceObjectivesThis study aims to evaluate the concordance between the disc diffusion test (DDT) and custom-designed Sensititre® Broth Microdilution plates and to estimate their respective sensitivity and specificity for antimicrobial susceptibility testing (AST) of Bacteroides fragilis group (BFG) clinical isolates.MethodsAST was performed on 126 BFG isolates using both DDT and Sensititre® methods according to the 2024 CA-SFM guidelines. Cohen's kappa coefficients were used to assess concordance, while a Bayesian approach estimated sensitivity and specificity with 95 % confidence intervals (95 % CIs) for amoxicillin-clavulanate (AMC), piperacillin-tazobactam (PTZ), imipenem (IPM), clindamycin (CLI), metronidazole (MTR), and moxifloxacin (MXF).ResultsCohen's kappa coefficients with 95 % CIs for AMC, PTZ, IPM, CLI, MTR, and MXF were 0.92 (0.85–1.00), 0.70 (0.56–0.83), 0.96 (0.92–1.00), 0.98 (0.94–1.00), 0.96 (0.89–1.00), and 0.70 (0.58–0.82), respectively. DDT demonstrated sensitivity > 0.8 for all antibiotics, and specificity > 0.8 except for PTZ (0.51; 0.37–0.65) and CLI (0.71; 0.58–0.82). Sensititre® exhibited sensitivity > 0.9 for all antibiotics except for PTZ (0.86; 0.70–0.99), and specificity > 0.9 except for MXF (0.88; 0.75–0.99).ConclusionsDDT and Sensititre® Broth Microdilution demonstrated strong concordance for most antibiotics. Predictive values estimated using Bayesian model showed that Sensititre® offered the highest overall sensitivity and specificity