HAL-Pasteur
Not a member yet
19256 research outputs found
Sort by
Global dynamics of antibiotic resistance: a modeling study of the spread of endemic and emerging resistance in E. coli
No full textBackground Antibiotic resistance (ABR) poses a growing threat at the global level. Emergence and worldwide dissemination of multi-resistant clones are frequently reported. However, associated drivers are still largely unknown and are a crucial knowledge to mitigate ABR risk in humans. Methods We used mechanistic modeling to analyze annual trends of extended-spectrum β-lactamase-producing Escherichia coli (ESBL-EC) in 39 countries over 2006-2019. The model formalizes ESBL-EC transmission, colonization and infection at the country and global levels, accounting for heterogeneous antibiotic prescriptions and human mobility. The fitted model is used to explore hypothetical scenarios of emerging antibiotic-resistant clones like carbapenem-resistant E. coli (CR-EC) and evaluate their global dissemination risk. Findings International travels alone do not explain heterogeneous ESBL-EC dynamics. Reproducing observed trends requires accounting for antibiotics impact on ESBL-EC acquisition and heterogeneous within-country transmission rates. Strong differences in transmission rates are inferred between Europe and South-East Asia, ranging on average from 7.05×10 - 3 day -1 in Spain to 16.21×10 -3 day -1 in Thailand. For CR-EC, spatiotemporal dynamics depends on the explored emergence scenario. We show that mobility patterns drive 5-years resistance dynamics, while 20-years dynamics are mostly predicted by within-country transmission and antibiotic use. Interpretation This spatiotemporal analysis highlights the weight of international travel in the early global dissemination of antibiotic-resistant clones but suggests that reducing transmission and selection pressure is fundamental to avoid fixation. There is a need to strengthen surveillance and data collection of community colonization and infection to refine modeling and support decision and ABR control at the global scale. Funding Pfizer independent medical grant (number 57504809
Pneumococcus uses COMMD2 to alter host cellular immunity
No full textNF-κB driven cellular immunity is essential for both pro- and anti-inflammatory responses to microbes, which makes it one of the most frequently targeted pathways by bacteria during pathogenesis. How NF-κB tunes the epithelial response to Streptococcus pneumoniae across the spectrum of commensal to pathogenic outcomes is not fully understood. In this study, we compare a commensal-like 6B ST90 strain to an invasive TIGR4 isolate and demonstrate, through comparative mass spectrometry of the p65 interactome, TIGR4 challenge triggers a novel interaction of COMMD2 with p65 and p62. Mechanistically, we show this complex mediates export of p65 for degradation and COMMD2 is necessary for altering host cellular immunity. With these results, we reveal for the first time a new bacterial pathogenesis mechanism to repress host inflammatory response though COMMD2 and p65 degradation while presenting a paradigm for diverging NF-κB responses to pneumococcus
Bridging Language Phenotypes, Neural Dynamics and Gene Regulation in Autism
No full textAutism Spectrum Disorders (ASDs) affect approximately 1% of the global population, with prevalence rising over recent decades. While ASDs are strongly heritable (~70%), translating genetic findings into effective therapeutics remains challenging due to the vast number of implicated risk genes (>700) and their limited influence in disease expression. Current interventions remain symptom-focused and do not explicitly address underlying neurodevelopmental mechanisms. Emerging approaches in functional genomics offer new insights into ASD pathogenesis by exploring the diversity of gene expression, yet clinical applications remain distant. Language deficits are among the most frequent and disabling features of ASD, profoundly affecting the individual's and family's quality of life. Recent evidence from neuroimaging and electrophysiology studies suggest that disrupted and atypical neural oscillationsrhythmic brain activity patterns -dynamics are linked to language deficits in ASD.Importantly, several ASD-associated genes modulate brain oscillatory dynamics, pointing to a potential mechanistic link between genetic variation, altered brain rhythms, and language impairment. In this perspective article, we propose an imaging genetics framework that leverages neural oscillatory profiles as both endophenotypes relevant for targeted treatment and functional readouts of gene expression. Specifically, we advocate the use of neuromodulation to target and treat altered oscillatory dynamics underlying speech communication deficits in ASD, and the integration of oscillation-related ASD candidate genes into a new, symptom-oriented model of functional genomics. This approach illustrates how bridging genetic variation, non-invasive neuroimaging, and behavioral phenotypes can advance our understanding of ASD and inform the development of targeted, mechanism-based interventions.</p
Complement activation drives a compartmentalized innate immune response in C3 glomerulopathy contributing to the disease phenotype
No full textInternational audienceIntroduction: C3 glomerulopathy is a rare kidney disease resulting from dysregulation of the complement alternative pathway. The mechanistic diversity of alternative pathway activation, the heterogeneous immunological and clinical profiles limit a comprehensive understanding of the disease.Methods: Here, we characterize mechanisms of complement-mediated immune response within the kidney. We studied a retrospective cohort of 47 patients diagnosed with C3 glomerulopathy and profiled systemic and intra-kidney complement activation and characterized intra-kidney immune infiltrates.Results: The immune infiltrate of the kidney showed distinct compositions between the glomerular and interstitial compartments, with most neutrophils and macrophages in the glomeruli versus a majority of B and T lymphocytes and macrophages in the interstitium. The presence of a neutrophil-rich glomerular infiltrate appeared to be associated with stronger markers of complement activation in both systemic and intra-kidney compartments. However, interstitial immune infiltrates were not associated with a specific complement activation profile. The presence of a neutrophil-rich glomerular infiltrate correlated with a better response of the kidney to treatment and kidney survival, while patients with higher interstitial infiltrate had poor kidney survival.Conclusion: Our study highlights a link between the intra-kidney immune response, complement activation profile, and the phenotypic expression of the disease, which contributes to improving our understanding of the disease
Novel circoviruses identified in short-finned pilot whale and orca from the North Atlantic Ocean
No full textInternational audienceThe family Circoviridae comprises viruses with small single-stranded DNA genomes that are known to infect various animals, resulting in considerable morbidity and mortality in some hosts. Circoviruses have been recently identified through metagenomic sequencing in diverse terrestrial vertebrate species, but their distribution and diversity in marine vertebrates remains underexplored. Here, we use high-throughput sequencing (HTS) to identify circoviruses from archived tissue samples of delphinids (order Artiodactyla, infraorder Cetacea, family Delphinidae). Based on the HTS data, we designed specific abutting primer pairs to recover seven complete circovirus genomes from individual delphinid hosts, namely, the short-finned pilot whale (Globicephala macrorhynchus, n = 5) and the orca (Orcinus orca, n = 2). The circoviruses from the two delphinid species share <65.4 % genome-wide pairwise nucleotide identity with all classified circovirus representative sequences and 66 % amongst themselves. Accordingly, these viruses, which we have named shofin circovirus and orcin circovirus, respectively, represent two novel species. This report also marks the first detection of cetacean circoviruses in the North Atlantic Ocean (near St. Vincent, Caribbean). Notably, analysis of the capsid protein sequences and structures of the delphinid circoviruses revealed notable elaborations within the surface exposed loops that have been previously shown to be a major antigenic epitope in porcine circovirus 2. Collectively, the delphinid circovirus genomes expand the known diversity of circoviruses of marine vertebrates and suggest similar evolutionary pressures exerted by the immune systems of cetacean and suina hosts, both members of the order Artiodactyla
Splenic accumulation of intact Plasmodium ovale sensu lato-infected red blood cells in a patient presenting with splenic rupture
No full textInternational audienceA 35-year-old man had splenic rupture just after starting antimalarial treatment with atovaquone-proguanil followed by artesunate for acute Plasmodium ovale sensu lato infection. Spleen histology showed a 10-fold accumulation of intact P. ovale s.l. -infected erythrocytes in the spleen parenchyma compared to the general circulation. Infected erythrocytes also accumulated in small extra-splenic blood vessels, suggesting cytoadherence
Socio-demographic, provider-related and attitudinal determinants towards HPV vaccination in a French Caribbean territory
No full textSince introduction of Human Papillomavirus Vaccination (HPVV) in the French Caribbean in 2007, complete-schedule vaccine coverage at age 15 years among girls has remained below 25%, while national and international recommendations target at least 60%. We explored the parental socio-demographic, provider-related and attitudinal determinants of HPVV awareness, uptake and intention in Guadeloupe.Material and methodsWe conducted a cross-sectional survey among parents of adolescents enrolled in public and private middle schools in Guadeloupe in June 2023, using an online questionnaire sent out by schools. We developed separate multivariable logistic regression models predicting HPVV awareness, uptake and intention according to socio-demographic characteristics, HPVV offer by the general practitioner and attitudes towards HPVV.Results : A total of 306 parents completed the online survey questionnaire. Among them, 85.3% were aware of HPVV and 25.4% reported a child vaccinated with at least one dose of HPV vaccine. HPVV awareness was associated with parental educational attainment (OR=2.8;95%CI:[1.2-6.6]). HPVV uptake was associated with the child’s sex (for female, OR=3.6;95%CI:[2.0-6.5]). This latter association was mediated by medical HPVV offer, which itself was a strong determinant of uptake (OR=28.8;95%CI:[11.2-73.7]). Among parents aware of HPVV reporting an unvaccinated child, 27.0% intended vaccination. The only significant determinant for this was having received a medical offer of HPVV (HPVV (OR= 2.3;95%CI:[1.1-4.8]). Believing that the child was too young to be vaccinated was stongly associated with both vaccine uptake (OR=0.1;95%CI:[0.1–0.2]) and intention (OR=0.2;95%CI:[0.1–0.9]).Discussion and conclusions : These results suggest that public intervention through medical offer of HPVV holds a central place in HPVV uptake and intention among parents in Guadeloupe. This finding emphasizes the need for communication on the benefits and risks of HPVV and incentives to GPs to fully get involved in HPVV promotion, possibly with programmatic support from school-based campaigns promoting early vaccination
Decoding the biogenesis of HIV-induced CPSF6 puncta and their fusion with the nuclear speckle
No full textInternational audienceViruses rely on host cellular machinery for replication. After entering the nucleus, the HIV genome accumulates in nuclear niches where it undergoes reverse transcription and integrates into neighboring chromatin, promoting high transcription rates and new virus progeny. Despite anti-retroviral treatment, viral genomes can persist in these nuclear niches and reactivate if treatment is interrupted, likely contributing to the formation of viral reservoirs. The post-nuclear entry dynamics of HIV remain unclear, and understanding these steps is critical for revealing how viral reservoirs are established. In this study, we elucidate the formation of HIV-induced CPSF6 puncta and the domains of CPSF6 essential for this process. We also explore the roles of nuclear speckle scaffold factors, SON and SRRM2, in the biogenesis of these puncta. Through genetic manipulation and depletion experiments, we demonstrate the key role of the intrinsically disordered region of SRRM2 in enlarging nuclear speckles in the presence of the HIV capsid.We identify the FG domain of CPSF6 as essential for both puncta formation and binding to the viral core, which serves as the scaffold for CPSF6 puncta. While the low-complexity regions (LCRs) modulate CPSF6 binding to the viral capsid, they do not contribute to puncta formation, nor do the disordered mixed charge domains (MCDs) of CPSF6. These results demonstrate how HIV evolved to hijack host nuclear factors, enabling its persistence in the host.Of note, this study provides new insights into the underlying interactions between host factors and viral components, advancing our understanding of HIV nuclear dynamics and offering potential therapeutic targets for preventing viral persistence
Leptospirosis Prevalence and Risk Factors Among Patients Presenting With Fever to 4 Healthcare Sites in Sub-Saharan Africa and South East Asia: An International Multisite Observational and Nested Case-Control Study
No full textInternational audienceBackgroundWe investigated the prevalence, diversity, and risk factors for acute leptospirosis in the Febrile Illness Evaluation in a Broad Range of Endemicities (FIEBRE) study.MethodsFebrile patients aged ≥2 months in Laos, Malawi, Mozambique, and Zimbabwe underwent a standardized clinical and exposure assessment. Acute and convalescent serum were tested by Leptospira microscopic agglutination test (MAT) and acute plasma by lfb1 polymerase chain reaction. A ≥4-fold rise in antibody titer, or a single reciprocal titer ≥800, or Leptospira PCR positive defined confirmed leptospirosis. The identity of possible infecting strains was investigated by MAT and sequencing of PCR products.ResultsOf 7851 febrile participants enrolled, 134 (1.7%) had confirmed leptospirosis: 88 (4.6%) in Laos, 17 (1.0%) Malawi, 7 (0.3%) Mozambique, and 22 (1.2%) Zimbabwe, and 23 (0.8%) had supportive evidence of leptospirosis. Participants with leptospirosis had greater odds of headache (adjusted odds ratio [aOR] 2.20, P < .001), rash (aOR 1.45, P < .001), conjunctivitis (aOR 3.33, P < .001), and jaundice (aOR 1.75, P < .001); and had greater odds of being older (aOR 1.02 per year, P < .001), working in rice fields (aOR 6.24, P < .001), drinking river water (aOR 5.11, P = .001). Predominant reactive Leptospira serogroups were Ballum and Icterohemorrhagiae at African sites, and Australis in Laos. Identified species were Leptospira borgpetersenii, L. interrogans, and L. kirschneri.ConclusionsLeptospirosis was a cause of febrile illness at all sites. Some clinical features helped to identify patients with leptospirosis. Interventions related to rice field work and river exposure may prevent disease. Diverse Leptospira serogroup reactivity was observed and may suggest potential hosts
[Chapter 60] Foamy Viruses
No full textInternational audienceFoamy viruses (FVs) are complex retroviruses. They infect numerous mammalian species, in particular nonhuman primates (NHPs). All simian and prosimian species tested to date harbor exogenous FVs. They exhibit a broad tropism with respect to both cell and host species type. Human beings are not natural hosts for FV, but transmissions from monkeys to man do occur. Like all other retroviruses, FVs establish lifelong persistent infections. According to current knowledge, FVs do not cause any obvious disease, be it within the species of origin or after cross-species transmissions including zoonotic infections of humans. The FV replication cycle deviates from that of the orthoretroviruses, since several hallmarks set them apart from the latter. First, FV mRNA transcription is initiated from an internal promoter (IP), before the viral transactivator initiates expression of the other viral genes transcribed from the LTR-promoter. Second, the pol gene is translated as a separate protein rather than as a Gag-Pol polyprotein, a common characteristic of all other retroviruses. Third, the FV infectious genome consists of DNA rather than RNA with significant amounts of extracellular virions, obtained by in vitro propagation, carrying viral genomic DNA (vgDNA). Finally, with features unique to FVs, their replication includes characteristics from both orthoretroviruses and hepadnaviruses. Consequently, retroviral taxonomy comprises two retroviral subfamilies, the Orthoretrovirinae encompassing the bulk of retrovirus genera, and the Spumaretrovirinae containing five genera.The term “foamy” or latin “spuma” was coined in the 1950s to designate the virus after the observation of a distinct cytopathic effect (CPE) occurring in primary kidney cells derived from monkeys caught in the wild characterized by multinucleated syncytia and vacuolization causing a “foamy” appearance in vitro (Fig. 60.1; Video 60.1). This CPE was attributed to the latent infection of the donor monkeys with a transmittable agent, and eventually, became the light microscopy hallmark of in vitro FV propagation. The first decades of FV research dealt mainly with the identification of infected monkeys, and FVs were regarded as “common contaminants” until they were identified as retroviruses. Molecular cloning of a first FV permitted initial studies on their replication. With respect to their deviations from orthoretroviruses, their ability to cross host species barriers and their potential use as gene transfer systems, FVs are worthy of thorough investigation.This chapter summarizes our knowledge of FV epidemiology, cross-species transmission, virus evolution, and in-depth, their molecular, structural, and cellular biology. Here, we focus on FVs of NHPs and mention the nonprimate viruses if relevant depending to the scientific context