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Assessment of Plasmodium vivax transmission and asymptomatic carriage risk among artisanal gold miners in western French Guiana, 2014–2020
No full textInternational audienceBackground The final challenge for malaria elimination in many countries is to interrupt the circulation of Plasmodium vivax . Given the unique biology of this parasite, innovative approaches are imperative, with a focus on identifying asymptomatic carriers of dormant parasite forms. This article delineates the recent epidemiological patterns of P. vivax malaria within a highly mobile and hard-to-reach population in the Guiana Shield. It further proposes an assessment of the potential reservoir of asymptomatic carriers. Methods This analysis was based on data from: (i) two cross-sectional surveys carried out at the French-Surinamese border in 2015 and 2019, including adults returning from gold mining sites located in French Guiana (FG), [questionnaires and blood samples, tested for polymerase chain reaction (PCR) and P. vivax serological exposure markers (SEM) of recent infection]; (ii) epidemiological malaria surveillance system in Suriname, including cases imported from gold mining sites located in western FG between 2014 and 2020. Factors associated with P. vivax seropositivity were analysed by multiple logistic regression. The probability of carrying P. vivax parasites (blood-stage or hypnozoite) was estimated by a classification drawn from PCR results, SEM and reported recent history of illness. Results Surveillance data showed a decrease in malaria imported cases from French Guiana between beginning and end of the analysed period (236 in 2014 to 74 in 2020) and an increase in the proportion of cases associated with P. vivax (52.4% in 2014 to 100% in 2020). The PCR-prevalence of P. vivax in survey samples decreased from 11.4% in 2015 to 4.0% in 2019; P. vivax seropositivity decreased from 44.7% to 28.4%. P. vivax seropositivity was positively associated with male sex, age and number of years spent in gold mining, type of activity, and reported malaria history (episode within less than nine months OR = 10.73, 95% CI : 5.87–19.6, or history of repeated older episodes OR = 5.31, 95% CI : 3.13–9.01). Conclusions Our analysis shows an epidemiological evolution typical of a scenario of decreasing malaria circulation. Nevertheless, in 2020, gold miners in western FG still showed a moderate level of P. vivax circulation. Biological methods and epidemiological criteria can help to select potential parasite carriers, who could benefit from targeted drug administration
Cord Blood RSV-Neutralizing Antibodies and Risk of Hospitalization for RSV-Associated Acute Respiratory Infection in Vietnamese Children: A Case–Cohort Study
No full textInternational audienceBackground: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in children, particularly severe during infancy. Maternal RSV-specific neutralizing antibodies (nAbs), transferred via the placenta, may provide protection in early infancy, but the extent and duration of protection remain uncertain. Objective: We investigated the association between cord blood RSV-A nAb levels and the risk of hospitalization due to RSV-associated acute respiratory infection (RSV-ARI) by 24 months of age. Methods: We conducted a case–cohort study nested within a birth cohort in Nha Trang, Vietnam. From the full cohort (n = 1977), a random subcohort of 392 infants and all 66 infants hospitalized for RSV-ARI by age 24 months were included for RSV-A nAb testing. RSV-A nAb titers at birth were categorized into three groups in the subcohort (low: lowest quartile; middle; interquartile; high: highest quartile). Weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) for RSV-ARI hospitalization. Results: The incidence of RSV-ARI hospitalization was 17.92 per 1000 person-years by 24 months, and 25.40 per 1000 person-years among infants aged <12 months. Among infants aged <6 months, those in the low nAb group had a significantly higher risk of hospitalization compared to the middle nAb group (adjusted HR: 4.05; 95% CI: 1.51–10.89). Maternal anemia was consistently associated with increased risk. Conclusions: Lower RSV-nAb titers at birth were associated with an increased risk of RSV-ARI hospitalization during early infancy. These findings support the importance of maternal immunization strategies to enhance infant protection against RSV
A dual interaction between RSV NS1 and MED25 ACID domain reshapes antiviral responses
No full textInternational audienceRespiratory syncytial virus (RSV), the most common cause of bronchiolitis and pneumonia in infants, elicits a remarkably weak innate immune response. This is partly due to type I interferon (IFN) antagonism by the non-structural RSV NS1 protein. It was recently suggested that NS1 could modulate host transcription via an interaction with the MED25 subunit of the Mediator complex. Previous work emphasized the role of the NS1 C-terminal helix α3 for recruitment of the MED25 ACID domain, a target of transcription factors (TFs). Here we show that the NS1 α/β core domain binds to MED25 ACID and acts cooperatively with NS1 α3 to achieve nanomolar affinity. The strong interaction is rationalized by the dual NS1 binding site on MED25 ACID predicted by AlphaFold and confirmed by NMR, which overlaps with the two canonical binding interfaces of TF transactivation domains. Single amino acid substitutions in the NS1 α/β domain, notably NS1 E110A, significantly reduced the affinity of NS1 for MED25 ACID, both in vitro and in cellula. These mutations resulted in attenuated replication of recombinant RSV (rRSV-mCherry). They did not significantly upregulate type I or III IFN levels in IFN-competent BEAS-2B cells, contrary to the NS1 α3 deletion. However, in line with attenuated replication, the NS1 E110A mutation enhanced expression of the antiviral interferon-stimulated gene ISG15, and NS1 I54A upregulated ISG15, OAS1A and IFIT1 in IFN-competent cells. In MED25-knockdown cells, rRSV-mCherry replication was further attenuated at a late post-infection timepoint. The difference between WT and NS1 mutant rRSV-mCherry was partially lost, suggesting that the NS1–MED25 ACID complex contributes to controlling antiviral responses at this timepoint. The strong interaction and the extended binding interface between NS1 and MED25 ACID provide evidence for a mechanism, where NS1 blocks access of transcription factors to MED25, and thereby MED25-mediated transcription activation
Beta-cell adaptation unveiled: The role of myokines in insulin-resistant mice
No full textInternational audiencePancreatic beta cells can adapt their mass and function to maintain normal glycemia when facing peripheral insulin resistance. To clarify the specific contribution and mechanisms of beta-cell mass adaptation in response to insulin resistance, we took advantage of genetic and pharmacologically induced insulin resistance in mice. We uncovered beta-cell expansion, via an increase in pancreatic islet density, as an adaptive mechanism triggered by mild-to-severe insulin resistance in young and older mice and documented pancreatic adaptation using 3D whole-pancreas analysis. Next, we found that insulin-resistant myotubes secrete factors that induce beta-cell differentiation. Using a combination of transcriptomic and functional analysis on a pancreatic differentiation model, we identified that myostatin, amphiregulin, and epiregulin can induce beta-cell differentiation in vitro. This work highlights how a physiological adaptation to insulin resistance can unlock the regenerative potential of myotube-derived peptides to trigger adaptive pancreatic beta-cell mass increase
Interaction des protéines Pyk2 et Bin1, toutes deux associées à des facteurs de risque génétique de la Maladie d’Alzheimer
No full textAlzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline, memory disturbances, and significant synaptic alterations. Although AD is generally considered sporadic, numerous studies have revealed a strong genetic component in its development. In particular, genome-wide association studies (GWAS) have identified over 70 genetic loci associated with an increased risk of developing the disease. Among these, the BIN1 gene (Bridging Integrator 1), a major player in synaptic dynamics and protein Tau regulation, holds a prominent position, ranking second after the APOE gene in genetic risk factors for AD. At the same time, the gene PTK2B, which encodes a non-receptor tyrosine kinase (Pyk2), has also been identified as a genetic risk factor for AD, although its role in the physiopathology of the disease remains poorly understood. The aim of my thesis was to better understand the functional role of BIN1 and Pyk2 in AD by specifically exploring the interaction between these two proteins and comparing this interaction with that of Pyk2's paralog Fak1, which is not directly linked to AD. This comparison aimed to clarify the molecular mechanisms of the BIN1-Pyk2 interaction.Initially, I performed the production and purification of recombinant proteins (Chapter 1). This step allowed us to obtain highly pure proteins, which were essential for the subsequent structural and biophysical experiments. This limiting step has required extensive optimization of protocols, it was a crucial part of the project.A significant portion of my thesis focused on studying the conformation of the KFL linker, an intrinsically disordered region linking the Kinase and FAT domains in the focal adhesion kinases Pyk2 and Fak1. We used Nuclear Magnetic Resonance (NMR) spectroscopy to assign the chemical shifts of the KFL, which allowed us to define their conformational properties. The analysis revealed that, although predominantly disordered, the KFL region contains segments that are capable of adopting α-helices, modeled to form homo-dimeric interfaces. We demonstrated that coil-coil interactions between these helices promote the assembly of heterogeneous multimers. Additionally, we observed that the KFL form condensates in vitro under high crowding conditions. Our results showed that the KFL undergo phase separation, a key biological process related to protein clustering. Finally, by comparing the conformational properties of the KFL domains of Pyk2 and Fak1, we gained a better understanding of the structural basis of their interactions.In parallel, I studied the interaction between BIN1 and the kinases Pyk2 and Fak1. Pulldown experiments with GST-fusion domains of Pyk2 and Fak1 confirmed these interactions with BIN1 isoforms 1 and 9, which were then validated by NMR. The NMR experiments, thanks to the NMR assignments, has allowed to identify the interaction sites between the SH3 domain of BIN1 and the proline-rich peptides (PRR) of the KFL of Pyk2 and Fak1.Our structural and biophysical analyses revealed that BIN1-SH3 exhibits differential affinity for these sequences and modulates the LLPS properties of the KFL. I also employed complementary techniques such as NMR, Isothermal Titration Calorimetry (ITC), and Surface Plasmon Resonance (SPR) to quantify the affinity of these interactions. These results provide a functional link between the role of BIN1 and the focal adhesion complex, via the regulation of focal kinase signalling. We show that these proteins interact within the same signaling pathway, suggesting their involvement in the focal adhesion complex, with implications for their role in the physiopathology of AD.La maladie d'Alzheimer (MA) est une pathologie neurodégénérative complexe, caractérisée par un déclin cognitif progressif, des troubles de la mémoire, et des altérations synaptiques majeures. Bien que la MA soit généralement considérée comme sporadique, de nombreuses études ont révélé une forte composante génétique dans son développement. En particulier, les études d'association pangénomiques (GWAS) ont permis d'identifier plus de 70 loci génétiques associés à un risque accru de développer la maladie. Parmi ceux-ci, le gène BIN1 (Bridging Integrator 1), un acteur majeur dans les dynamiques synaptiques et la régulation de la protéine Tau, occupe une place prépondérante, se classant en second après le gène APOE dans les facteurs de risque génétiques de la MA. En parallèle, le gène PTK2B, qui code pour une tyrosine kinase non associée à un récepteur (Pyk2), a également été identifié comme un facteur de risque génétique pour la MA, bien que son implication dans la physiopathologie de la maladie demeure encore mal comprise. L'objectif de ma thèse a été de mieux comprendre le rôle fonctionnel de BIN1 et Pyk2 dans la MA, en explorant spécifiquement l'interaction entre ces deux protéines, et en comparant cette interaction avec celle du paralogue de Pyk2, Fak1, qui ne présente pas de lien direct avec la MA. Cette comparaison vise à clarifier les mécanismes moléculaires de l'interaction BIN1- Pyk2. Dans un premier temps, j’ai réalisé la production et la purification de protéines recombinantes (Chapitre 1). Cette étape a permis d’obtenir des protéines avec un haut degré de pureté, essentielles aux expériences structurales et biophysiques menées par la suite. Cette étape limitante a nécessité beaucoup de temps d’optimisation de protocoles. Une part importante de ma thèse a été consacrée à l’étude de la conformation du linker KFL, une région intrinsèquement désordonnée reliant les domaines Kinase et FAT dans les kinases d'adhésion focale Pyk2 et Fak1. Nous avons utilisé la Résonance Magnétique Nucléaire (RMN) pour attribuer les déplacements chimiques des KFL, ce qui nous a permis de définir leurs propriétés conformationnelles. L'analyse a révélé que, bien que principalement désordonnée, la région KFL contient des segments capables d’adopter des hélices α, modélisées pour former des interfaces homo-dimériques. Nous avons montré que les interactions coil-coil entre ces hélices favorisent l'assemblage de multimères hétérogènes. De plus, nous avons observé que les KFL forment des condensats in vitro sous des conditions de « crowding » moléculaire. Nos résultats montrent que les segments KFL isolés subissent une séparation de phase, un processus biologique clé lié au regroupement des protéines. Enfin, en comparant les propriétés conformationnelles des domaines KFL de Pyk2 et Fak1, nous avons acquis une meilleure compréhension de la base structurelle de leurs interactions. En parallèle, j’ai étudié l’interaction entre BIN1 et les kinases Pyk2 et Fak1. Des expériences de « pull-down » avec des domaines fusionnés GST de Pyk2 et Fak1 ont confirmé ces interactions avec les isoformes 1 et 9 de BIN1, validées ensuite par RMN. Les expériences de RMN, grâce aux attributions réalisées, ont permis d’identifier les sites d’interaction entre le domaine SH3 de BIN1 et les peptides riches en proline (PRR) des KFL de Pyk2 et Fak1. Nos analyses structurales et biophysiques ont révélé que BIN1-SH3 présente une affinité différentielle pour ces séquences et modifie les propriétés de séparation de phase liquide-liquide (LLPS) des KFL. J’ai aussi utilisé des techniques complémentaires telles que la RMN, la Calorimétrie de Titration Isotherme (ITC) et la Résonance Plasmonique de Surface (SPR) pour quantifier l’affinité de ces interactions. Ces résultats permettent de faire un lien fonctionnel entre BIN1 et le complexe d’adhésion focale, par l’intermédiaire de la régulation de la signalisation des kinases focales [...]
Multinuclear non-haem iron-dependent oxidative enzymes: landscape of their substrates, partner proteins and biosynthetic gene clusters
No full textInternational audienceProteins of the multinuclear non-haem iron-dependent oxidative (MNIO) enzyme superfamily catalyse various modification reactions on the precursors of ribosomally synthesized post-translationally modified peptides (RiPPs). We recently identified two large families of MNIO-modified RiPPs called bufferins, which enhance bacterial growth under copper stress by chelating the excess metal ions. Here, we explored the diversity of potential MNIO substrates by performing extensive in silico studies. Analyses of MNIO-coding biosynthetic gene clusters (BGCs) identified various groups of putative precursors, most of which are characterized by specific Cys-containing motifs, throughout the eubacterial phylogenetic tree. The precursors of most MNIO-modified RiPPs harbour N-terminal Sec-dependent signal peptides, a rare feature among bacterial RiPPs. Some precursors are very long relative to those of typical RiPPs, indicating that MNIO enzymes could modify both peptide and protein substrates. We also identified a distinct family of integral membrane proteins with large predicted extra-cytoplasmic domains mostly found in Actinomycetota , frequently but not systematically associated with MNIOs. Most MNIO BGCs harbour genes coding for DUF2063 domain-containing proteins or structurally related proteins, serving as partners of the enzymes for precursor modification. We uncovered a correlation between the presence or the absence of Sec signal peptides in the precursors and the types of partner proteins of the MNIO enzymes. This study depicts the global landscape of potential MNIO-dependent natural products by unveiling groups of peptides and proteins genetically associated with MNIOs. It reveals a treasure trove of potential new RiPP precursors which likely represent a widespread bacterial strategy to deal with copper stress, and most likely other stresses, in natural environments
Bone, a double victim in metastatic catecholamine secreting tumors
No full textInternational audienceIntroductionBenign catecholamine-secreting pheochromocytoma and paraganglioma (PPGL) can cause secondary osteoporosis. Metastatic PPGLs, often presenting with bone metastases, elevated catecholamine levels and persistent disease, may lead to more severe bone impact. We investigated bone density and quality in three cases of metastatic PPGL over long-term follow-up.PatientsTwo patients had paragangliomas: a 43-year-old with an SDHB-related abdominal paraganglioma secreting norepinephrine, and a 35-year-old with an aggressive SDHA-related paraganglioma secreting both norepinephrine and dopamine. The third patient, aged 50 years, had a sporadic pheochromocytoma producing norepinephrine and dopamine. Bone mineral density (BMD) and quality were studied using dual-energy X-ray absorptiometry (DXA). The 43-year-old and 35-year-old patients exhibited lumbar and hip osteoporosis. The 43-year-old patient also showed changes in the trabecular bone score (TBS) and suffered from both osteoporotic and metastatic vertebral fractures. The 50-year-old patient had a mildly reduced hip T score but no TBS impairment. Additionally, the 35-year-old patient underwent high-resolution peripheral quantitative computed tomography (HR-pQCT), revealing a moderate decline in total BMD in the right tibia and reduced trabecular thickness in the left radius, although there were no vertebral fractures. This patient was treated shortly after diagnosis by bone resorption inhibitors, due to metastatic vertebral fractures.ConclusionsImpaired bone density and quality, possibly related to long-term exposure to catecholamine excess, contribute to skeletal-related events in metastatic PPGL. Recognizing these complications is important for patient management
Genetic fingerprints derived from genome database mining allow accurate identification of genome-edited rice in the food chain via targeted high-throughput sequencing
No full textData availability: Raw whole-genome sequencing data and amplicon sequencing data is available in the European Nucleotide Archive under project accession number PRJEB84921.International audienceHighlights: • Genome-edited (GE) organisms fall currently below European GMO legislation. • Identifying GE organisms with single nucleotide variations remains challenging. • Genetic fingerprints were created via whole-genome sequencing and machine learning. • Targeted high-throughput sequencing to detect genetic fingerprints was developed.Abstract: Genome-edited (GE) organisms are currently classified as GMOs according to European legislation, requiring traceability and labelling in the food and feed supply chain. However, unambiguous identification of a specific GE organism with one or more induced single nucleotide variations (SNVs) dispersed across the genome remains challenging. This study explored whole-genome sequencing-based characterization, public genome databases, and machine learning tools to select key genetic elements and create a unique fingerprint for distinguishing a specific GE line. As a case study, a GE Nipponbare rice line containing a single CRISPR-Cas-induced SNV was used. To experimentally assess the detection of this fingerprint, a targeted high-throughput sequencing approach, including multiplex PCR-based enrichment of key genetic elements, was developed and successfully tested. This promising proof-of-concept demonstrates the potential of combining a unique genetic fingerprint with targeted high-throughput sequencing to facilitate the accurate detection of GE organisms, thereby supporting food traceability and regulatory compliance for the development of new GE lines, as well as protecting associated intellectual property
Opinion of the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) on the risks to human health associated with the proliferation of Ostreopsis spp. on the Basque coast
No full textN/AInternational audienceIn France, the presence of marine microalgae of the genus Ostreopsis has been identified repeatedly on the Mediterranean coast for several years, whereas on the French Basque coasts its presence is much more recent. In the summers of 2021 and 2022, major Ostreopsis flowering episodes were reported on the Basque coast, resulting in several hundred cases of intoxication among holidaymakers and residents. The main route of human exposure is inhalation of aerosols, although it is not yet known whether the agents responsible for poisoning are Ostreopsis cells, cell debris, known toxins produced by Ostreopsis, or other as yet unidentified compounds. Other routes of exposure (dermal contact, eye contact, ingestion of contaminated water or seafood) are also possible. Poisoning is manifested through various signs and symptoms, occurring within 48 hours of exposure (Neurosensory and neurological, respiratory, dermal and digestive). This document presents the opinion of the French Agency for Food, Environmental and Occupational Health & Safety (ANSES), established from the work of its WATER and ERCA Expert Committees. ANSES received a request from the Directorate General for Health (DGS) and the Directorate General for Food (DGAL) to update knowledge about Ostreopsis that had been reported in the Agency's opinions from 2007 and 2008 (ANSES, 2007 and 2008), and draw up specific recommendations for managing Ostreopsis proliferation on the Basque coast. The literature review conducted as part of this expert appraisal revealed that knowledge about the genus Ostreopsis (diversity, biology, ecology, toxins produced) is still too fragmentary to characterise the hazard and risk to human health. Nevertheless to help local authorities affected by Ostreopsis blooms, Agency proposes a surveillance and quality monitoring strategy based on collaboration between site managers and the regional health agencies (ARSs), applicable to sites currently subject to bathing water quality monitoring and water sports sites that meet the conditions below
Native-to-invasive rodent species turn-over within African cities: The example of Niamey, Niger
No full textInternational audienceExpanding transportation infrastructure has facilitated the introduction and proliferation of invasive small mammals, particularly now cosmopolitan rodents like Rattus spp. and Mus musculus, within urban socio-ecosystems where they may severely impact local biodiversity, economy and public health. However, fine-scale dynamics of such biological invasions are still poorly documented, especially in African cities where such biological invasions are still ongoing. We took advantage of a long-term monitoring program of terrestrial small mammal communities of Niamey, the capital city of Niger, to compare rodent and shrew faunas at the same sampling points ten years apart, namely in 2009-2013 and in 2020-2023. We show that Rattus rattus has been expanding significantly in almost all trapping areas across the city, while Mastomys natalensis relative abundance has decreased. This clear trend of native-toinvasive rodent species turnover was particularly marked within the core city, but some notable exceptions exist in peripheral as well as traditionally built zones where the native species still remains dominant. These patterns are discussed, with special attention given to possible human socio-economic and health implications.</div