Biology subjects

Pennetier, C.

Publications and source records attributed to Pennetier, C..

14 recordsLinked to original sources

bioRxiv2025

Selection of a Lead Long-Acting Formulation of Ivermectin to Target Major Malaria Vectors in Western Africa: Evaluation of Pharmacokinetics and Mosquitocidal Efficacy in Cattle under Laboratory Conditions.

BackgroundIvermectin, a semisynthetic endectocide, is widely used against parasitic nematodes in humans and animals. Its lethality to Anopheles mosquitoes after feeding on treated hosts represents a promising malaria control strategy, particularly against outdoor transmission. However, standard oral formulations for use in humans produce short-lived mosquitocidal blood concentrations, limiting epidemiological impact. To meet WHO Preferred Product Characteristics (PPC) for endectocides against malaria vectors (Hazard Ratios >4 for at least one month), three long-acting injectable ivermectin formulations (LAIFs) based on BEPO(R) depot technology were developed and compared in cattle to identify the most suitable candidate for future human use. MethodsA cattle-Anopheles model was used under laboratory conditions in Bobo-Dioulasso, Burkina Faso. Three LAIF candidates (mdc-STM-001, mdc-STM-002, mdc-STM-003) were injected to calves (n=5 per formulation) at 0.6 mg/kg, with untreated calves as controls (n=5). Plasma ivermectin concentrations were measured over 130 days and analyzed using non-compartmental pharmacokinetics. Direct skin feeding assays were conducted at 15 timepoints (days 2-126 post-injection) using insecticide-susceptible (KIS) and wild-derived resistant (VK5) Anopheles colonies. Efficacy was assessed through 10-day cumulative mortalities, hazard ratios, 50% lethal concentrations (LC50), and duration of exposure above the 10-day LC50, accounting for the extrinsic incubation period of Plasmodium falciparum. ResultsAll formulations were well tolerated. Mdc-STM-001 showed the most favorable pharmacokinetic profile, with a controlled peak concentration (Cmax = 34.5 {+/-} 12.7 ng/mL) and the lowest inter-individual variability (12%). Ten-day hazard ratios exceeded 4 and cumulative mortalities were >50% for at least 60 days in both strains. Median mosquito lifespan remained below 10 days for at least 90 days post-injection. The 10-day LC50 for resistant mosquitoes (3.66 [2.69-4.97] ng/mL) was maintained for [≥]126 days. ConclusionThe Mdc-STM-001 was identified as the optimal candidate. A single injection induced sustained mosquitocidal efficacy for at least two months, achieving HR >4 against both susceptible and resistant Anopheles populations and meeting WHO PPC for malaria endectocides. Although extrapolation from cattle to humans requires caution, the favorable pharmacokinetic profile and robust entomological outcomes support progression to Phase 1 clinical trials. Ivermectins established safety record further strengthens the rationale for clinical development.

pathology↗

bioRxiv2023

Impact of blood meals taken on ivermectin-treated livestock on survival and fecundity of the malaria vector Anopheles coluzzii under laboratory conditions

Treatment of livestock with endectocides such as ivermectin is viewed as a complementary vector control approach to address residual transmission of malaria. However, efficacy of this treatment may vary between animal species. Hence, our purpose was to investigate the effects of ivermectin treatments of common livestock species on life history traits of the opportunistic malaria vector Anopheles coluzzii. Sheep, goats and pigs were treated using injectable veterinary ivermectin formulation at the species-specific doses (recommended dose for all species and high dose in pig). Mosquito batches were exposed to treated and control (not injected) animals at different days after treatment. Daily mosquito mortality was recorded and fecundity assessed through the count of gravid females and the number of eggs they developed. The recommended dose of ivermectin induced a significant decrease in mosquito survival for up to 7 days after injection (DAI), with a decrease of 89.7%, 66.7%, and 48.4% in treated pigs, goats and sheep, respectively, compared to control animals. In treated pigs, the triple therapeutic dose decreased mosquito survival of 68.97% relatively to controls up to 14 DAI. The average number in gravid females Anopheles that survived after feeding on treated animals were reduced when blood-meals were taken on sheep (2.57% and 42.03% at 2 and 7 DAI), or on goats (decrease of the 28.28% and 73.64% respectively at 2 and 7 DAI). This study shows that ivermectin treatments to animals negatively impacts An. coluzzii life history traits and could reduce vector densities in areas where livestock live near humans. However, due to short-term efficacy of single dose treatments, repeated treatments and potentially increased dosages would be required to span the transmission season. The use of long-acting ivermectin formulations is discussed as a mean for extending efficacy while remaining cost effective.

systems biology↗

bioRxiv2023

Striking allelic diversity despite structural homogeneity of ace-1 duplications in Anopheles mosquitoes

A. gambiae s.l. has been the target of intense insecticide treatment since the mid-XXth century to try and control malaria, and a substitution in the ace-1 locus allowing resistance to organophosphate and carbamates insecticides has been rapidly selected for. Since then, several duplications of the ace-1 locus have been found in A. gambiae s.l. populations. They associate either several resistance copies (homogeneous duplications) or both resistance and susceptible copies (heterogeneous duplications). Heterogeneous duplications confer an intermediate trade-off between resistance in presence of insecticide and disadvantage in their absence. So far, and in striking contrast with C. pipiens mosquitoes, a single heterogeneous duplication had been describe in A. gambiae populations. We use an innovative approach, combining information from long and short read sequencing with Sanger sequencing to precisely identify and describe at least nine different heterogeneous duplications in A. gambiae. We further show that these alleles share the exact same structure than the previously identified heterogeneous and homogeneous duplications, namely 203-kb tandem amplifications with conserved breakpoints. Our study sheds a new light on the origin and maintenance of these alleles in A. gambiae populations, and pushes one step further the striking evolutionary convergence with C. pipiens mosquitoes.

evolutionary biology↗

bioRxiv2022

Insecticide resistance and biting behaviour of malaria vectors in rural West-Africa : a data mining study to adress their fine-scale spatiotemporal heterogeneity, drivers, and predictability

AO_SCPLOWBSTRACTC_SCPLOWInsecticide resistance and behavioural adaptation of malaria mosquitoes affect the efficacy of long-lasting insecticide nets - currently the main tool for malaria vector control. To develop and deploy complementary, efficient and cost-effective control interventions, a good understanding of the drivers of these physiological and behavioural traits is needed. In this data-mining exercise, we modelled a set of indicators of physiological resistance to insecticide (prevalence of three target-site mutations) and behavioural resistance phenotypes (early- and late-biting, exophagy) of anopheles mosquitoes in two rural areas of West-Africa, located in Burkina Faso and Cote dIvoire. To this aim, we used mosquito field collections along with heterogeneous, multi-source and multi-scale environmental data. The objectives were i) to assess the small-scale spatial and temporal heterogeneity of physiological resistance to insecticide and behavioural resistance phenotypes, ii) to better understand their drivers, and iii) to assess their spatio-temporal predictability, at scales that are consistent with operational action. The explanatory variables covered a wide range of potential environmental determinants of vector resistance to insecticide or behavioural resistance phenotypes : vector control, human availability and nocturnal behaviour, macro and micro-climatic conditions, landscape, etc. The resulting models revealed many statistically significant associations, although their predictive powers were overall weak. We interpreted and discussed these associations in light of several topics of interest, such as : respective contribution of public health and agriculture in the selection of physiological resistances, biological costs associated with physiological resistances, biological mechanisms underlying biting behaviour, and impact of micro-climatic conditions on the time or place of biting. To our knowledge, our work is the first modeling insecticide resistance and feeding behaviour of malaria vectors at such fine spatial scale with such a large dataset of both mosquito and environmental data.

ecology↗

bioRxiv2021

Illuminati, a novel form of gene expression plasticity in Drosophila neural stem cells

With the aim of developing a genetic instability (GI) sensor in vivo we used the well-established Gal80/Gal4-UAS system combined with a visual GFP marker in Drosophila. We generated a collection of 25 Drosophila lines carrying GAL80 transgenes in different locations in all major chromosomes (X, Y, II, and III). We found low rates of GFP cells in epithelial tissues such as wing discs. In contrast, in larval brains, GFP positive clusters containing neural stem cells- also called neuroblasts (NBs)- and their offspring, were highly frequent. Using genetic and imaging-based approaches, we show that GFP NBs do not result from aneuploidy or mutations in the GAL80 gene, but rather by stochastic repression of GAL80 expression. We named this novel type of gene expression instability Illuminati. Importantly, Illuminati frequency is influenced by environmental and stress conditions. Further, we found that once established, Illuminati can be propagated over many cell cycles.

developmental biology↗

bioRxiv2021

Data-driven and interpretable machine-learning modeling to explore the fine-scale environmental determinants of malaria vectors biting rates in rural Burkina Faso

BackgroundImproving the knowledge and understanding of the environmental determinants of malaria vectors abundances at fine spatiotemporal scales is essential to design locally tailored vector control intervention. This work aimed at exploring the environmental tenets of human-biting activity in the main malaria vectors (Anopheles gambiae s.s., Anopheles coluzzii and Anopheles funestus) in the health district of Diebougou, rural Burkina Faso. MethodsAnopheles human-biting activity was monitored in 27 villages during 15 months (in 2017-2018), and environmental variables (meteorological and landscape) were extracted from high resolution satellite imagery. A two-step data-driven modeling study was then carried-out. Correlation coefficients between the biting rates of each vector species and the environmental variables taken at various temporal lags and spatial distances from the biting events were first calculated. Then, multivariate machine-learning models were generated and interpreted to i) pinpoint primary and secondary environmental drivers of variation in the biting rates of each species and ii) identify complex associations between the environmental conditions and the biting rates. ResultsMeteorological and landscape variables were often significantly correlated with the vectors biting rates. Many nonlinear associations and thresholds were unveiled by the multivariate models, both for meteorological and landscape variables. From these results, several aspects of the bio-ecology of the main malaria vectors were precised or hypothesized for the Diebougou area, including breeding sites typologies, development and survival rates in relation to weather, flight ranges from breeding sites, dispersal related to landscape openness. ConclusionsUsing high resolution data in an interpretable machine-learning modeling framework proved to be an efficient way to enhance the knowledge of the complex links between the environment and the malaria vectors at a local scale. More broadly, the emerging field of interpretable machine-learning has significant potential to help improving our understanding of the complex processes leading to malaria transmission.

ecology↗

bioRxiv2020

Drosophila neural stem cells show a unique dynamic pattern of gene expression that is influenced by environmental factors

With the aim of developing a sensor for chromosome loss in vivo, we used the well-established GAL4/GAL80 system combined with a visual GFP marker in Drosophila. We show a low frequency of green cells in most Drosophila tissues, suggesting low aneuploidy levels. Unexpectedly, in the brain, GFP positive cells are more frequent, but in this case, they do not represent chromosome loss. Using genetic manipulations, RNA FISH and time-lapse microscopy, we uncovered a dynamic and reversible silencing of GAL80 that occurs in Drosophila neural stem cells. Further, we showed that this novel gene expression regulation is influenced by environmental changes such as temperature variations or food composition. These results have important implications for the Drosophila community, namely the possible interpretation of false positive cells in clonal experiments. Additionally, they also highlight a level of mosaicism and plasticity in the brain, consistent with possible epigenetic regulation of fly chromosomes, which is different from other organs and tissues.

cell biology↗

bioRxiv2020

Insecticide resistance status of malaria vectors Anopheles gambiae s.l of southwest Burkina Faso and residual efficacy of indoor residual spraying with microencapsulated pirimiphos-methyl insecticide

The rapid spread of insecticide resistance in malaria vectors and the rebound in malaria cases observed recently in some endemic areas underscore the urgent need to evaluate and deploy new effective control interventions. A randomized control trial was conducted with the aim to investigate the benefit of deploying complementary strategies, including indoor residual spraying (IRS) with pirimiphos-methyl, in addition to long-lasting insecticidal nets (LLINs) in Diebougou, southwest Burkina Faso. We measured the susceptibility of Anopheles gambiae s.l. population from Diebougou to conventional insecticides. We further monitored the efficacy and residual activity of pirimiphos-methyl on both cement and mud walls using a laboratory susceptible strain (Kisumu) and the local An. gambiae s.l. population. An. Gambiae s.l. from Diebougou was resistant to pyrethroids (deltamethrin, permethrin and alphacypermethrin) and bendiocarb but showed susceptibility to organophosphates (pirimiphos-methyl and chlorpyrimiphos-methyl). A mixed-effect generalized linear model predicted that pirimiphos-methyl applied on cement or mud walls was effective for 210 days against the laboratory susceptible strain and 247 days against the local population. The residual efficacy of pirimiphos-methyl against the local population on walls made of mud was similar to that of cement (OR=0.792, [0.55-1.12], Tukeys test p-value =0.19). This study showed that one round of IRS with pirimiphos-methyl CS has the potential to control the multi-resistant An. gambiae s.l. population from Southwest Burkina Faso for at least 7 months, regardless of the type of wall.

systems biology↗

bioRxiv2019

Sub-lethal insecticide exposure affects host biting efficiency of Kdr-resistant Anopheles gambiae

AO_SCPLOWBSTRACTC_SCPLOWThe massive use of insecticide-treated nets (ITNs) has drastically changed the environment for malaria vector mosquitoes, challenging their host-seeking behaviour and biting success. Here, we investigated the effect of a brief exposure to an ITN on the biting behaviour of Anopheles mambiae mosquitoes and the interaction between such behaviour and the kdr mutation that confers resistance to pyrethroids. To this aim, we developed a video assay to study the biting behaviour of mosquitoes with similar genetic background, but different kdr locus genotypes (SS i.e. homozygous susceptible, RS i.e. heterozygous and RR i.e. homozygous resistant), after a brief exposure to either control untreated nets or one of two types of pyrethroid-treated nets (deltamethrin or permethrin). In presence of untreated nets, the kdr mutation did not influence mosquito blood feeding success but caused differences in feeding and prediuresis durations and blood meal size. Exposure to deltamethrin ITN decreased the blood feeding success rate of RR and RS mosquitoes, whereas in presence of permethrin ITN, the kdr mutation increased the blood-feeding success of mosquitoes. Exposure to the two types of pyrethroid-treated nets reduced feeding duration, prediuresis duration and blood meal size of all three genotypes. Our study demonstrates a complex interaction between insecticide exposure and the kdr mutation on the biting behavior of mosquitoes, which may substantially impact malaria vector fitness and disease transmission.

animal behavior and cognition↗

bioRxiv2019

Anopheles bionomic, insecticide resistance and malaria transmission in southwest Burkina Faso: a pre-intervention study

BackgroundThe present study presents results of entomological surveys conducted to address the malaria vectors bionomic, insecticide resistance and transmission prior to the implementation of new strategies complement long-lasting insecticidal nets (LLINs) in the framework of a randomized control trial in southwest Burkina Faso. MethodsWe conducted entomological surveys in 27 villages during the dry cold season (January 2017), dry hot season (March 2017) and rainy season (June 2017). We carried out hourly catches (from 17:00 to 09:00) inside and outside 4 houses in each village using the Human Landing Catch technique. Mosquitoes were identified using morphological taxonomic keys. Specimens belonging to the Anopheles gambiae complex and Funestus Group were identified using molecular techniques as well as detection of Plasmodium falciparum infection and insecticide resistance target-site mutations. ResultsEight Anopheles species were detected in the area. Anopheles funestus s.s was the main vector during the dry cold season. It was replaced by Anopheles coluzzii during the dry hot season whereas An. coluzzii and An. gambiae s.s. were the dominant species during the rainy season. Species composition of the Anopheles population varied significantly among surveys. All researched target site mutation of insecticide resistance (kdr-w, kdr-e and ace-1) were detected in all members of the An. gambiae complex of the area but at different frequencies. We observed early and late biting phenotypes in the main malaria vector species. Entomological inoculation rates were 0.087, 0.089 and 0.375 infected bites per human per night during dry cold season, dry hot season and rainy season, respectively. ConclusionThe intensity of malaria transmission was high despite the universal coverage with LLINs. We detected early and late biting phenotypes in the main malaria vector species as well as physiological insecticide resistance mechanisms. These vectors might mediate residual transmission. These data highlight the need to develop complementary tools in addition to LLINs in order to better control resistant malaria vectors and to monitor insecticide resistance.

epidemiology↗

bioRxiv2019

Anopheles bionomics, insecticide resistance mechanisms and malaria transmission in the Korhogo area, northern Cote d Ivoire: a pre-intervention study

BackgroundA better understanding of malaria transmission at a local scale is essential for developing and implementing effective control strategies. In the frame of a randomized control trial, we aimed to provide an updated description of malaria transmission in the Korhogo area, northern Cote dIvoire, and to get baseline data for the trial.\n\nMethodsWe performed Human Landing Collections in 26 villages in the Korhogo area during the rainy season (September-October 2016, April-May 2017) and the dry season (November-December 2016, February-March 2017). We used Polymerase chain reaction techniques to ascertain the species of the An. gambiae complex, Plasmodium sp sporozoite infection and insecticide resistance mechanisms in a subset of Anopheles vectors.\n\nResultsAnopheles gambiae s.l. was the predominant malaria vector in the Korhogo area. Overall, more vectors were collected outdoors than indoors (P < 0.001). Of the 774 An. gambiae s.l. tested in the laboratory, 89.65% were An. gambiae s.s. and 10.35% were An. coluzzii. The frequencies of the kdr allele were very high in An. gambiae s.s. but the ace-1 allele was found at moderate frequencies. An unprotected individual living in the Korhogo area received an average of 9.04, 0.63, 0.06 and 0.12 infected bites per night in September-October, November-December, February-March, and April-May, respectively.\n\nConclusionsThe intensity of malaria transmission is extremely high in the Korhogo area, especially during the rainy season. Malaria control in highly endemic areas such as Korhogo needs to be strengthened with complementary tools in order to reduce the burden of the disease.

zoology↗

bioRxiv2019

CELL CYCLE ASYNCHRONY GENERATES DNA DAMAGE AT MITOTIC ENTRY IN POLYPLOID CELLS

Polyploidy arises from the gain of complete chromosomes sets [1] and is known to promote cancer genome evolution. Recent evidence suggests that a large proportion of human tumours experience whole genome duplications (WGDs), which might favour the generation of highly abnormal karyotypes within a short time frame, rather than in a stepwise manner [2-6]. However, the molecular mechanisms linking whole genome duplication to genetic instability remain poorly understood. Further, possible mechanisms responsible for rapid genome reshuffling have not been described yet. Using repeated cytokinesis failure to induce polyploidization of Drosophila neural stem cells (NSCs, also called neuroblasts - NBs), we investigated the consequences of polyploidy in vivo. Here, we show that polyploid NSCs accumulate high levels of chromosome instability. Surprisingly, we found that DNA damage is generated in a subset of nuclei of polyploid NBs during mitosis, in an asymmetric manner. Importantly, our observations in flies were confirmed in mouse NSCs (mNSCs) after acute cytokinesis inhibition. Interestingly, DNA damage occurs in nuclei that were not ready to enter mitosis but were forced to do so when exposed to the mitotic environment of neighbouring nuclei within the same cell. Additionally, we found that polyploid cells are cell cycle asynchronous and forcing cell cycle synchronization is sufficient to lower the levels of DNA damage generated during mitosis. Overall, this work supports a model in which DNA damage at mitotic entry can generate a mutated genetic landscape that contributes to the onset of genetic instability.

cell biology↗

bioRxiv2019

Chromosomes function as a barrier to mitotic spindle bipolarity in polyploid cells

Whole genome duplications (WGDs) are found in a variety of tumors and are associated with chromosomal instability (CIN) and poor prognosis [1,2]. When induced experimentally, through cytokinesis failure, polyploid cells generate tumors [3]. Cytokinesis failure results in the accumulation of double DNA content, but also of cytoplasmic organelles, such as centrosomes, which are the major microtubule (MT) organizing centers of animal cells. Importantly, even if there is a correlation between polyploidy and CIN [4], the underlying mechanisms generating error-prone mitosis in cells with extra DNA and extra centrosomes are not known. When considering polyploid mitosis, it is essential to take into account the increase in MT nucleation due to the presence of extra centrosomes and extra DNA. The presence of supernumerary centrosomes in a cell, centrosome amplification [5], is associated with mitotic spindle multipolarity and CIN [6-9]. Importantly, additional MTs can be nucleated from the chromatin (chromatin mediated pathway-CMP) or from pre-existing MTs-through the Augmin pathway. We hypothesized that the increase in DNA and centrosome content in a cell could lead to an increased MT mass, which might account for abnormal mitosis described in polyploid cells [4, 10, 11, 12]. Using genetics, live imaging and modeling approaches, we investigated the mechanisms establishing multipolarity in vivo in polyploid cells. We found that MT nucleation from the centrosomes is the major contributor to multipolarity, while other pathways seem to play minor roles. Unexpectedly, we found that even if Ncd/HSET, plays an essential role in promoting centrosome clustering in early mitosis, the increase in chromosome mass associated with cytokinesis failure functions as a barrier to centrosome clustering into two main poles. Our work provides a mechanistic link between polyploidy and the generation of CIN.

cell biology↗

bioRxiv2017

Small-scale field testing of Alpha-cypermethrin water-dispersible granules in comparison with the recommended wettable powder formulation for indoor residual spraying against malaria vectors in Benin

BackgroudPyrethroids are the most common class of insecticide used worldwide for indoor residual spraying (IRS) against malaria vectors. Water-dispersible granules (WG) are a pyrethroid formulation to be applied after disintegration and dispersion in water with less risks of inhalation than using the usual wettable powder (WP) formulation. The objective of this small-scale field study was to evaluate efficacy and duration of insecticidal action of a new alpha-cypermethrin WG (250g a.i./Kg) against susceptible Anopheles gambiae in comparison with the WHO reference product (alpha-cypermethrin WP, 50g a.i./Kg) on the most common indoor surfaces in Benin.\n\nMethodsBoth formulations were applied at two target-dose concentrations in houses made of mud and cement in the Tokoli village in southern Benin. We measured the applied dose of insecticide by chemical analysis of filter paper samples collected from the sprayed inner walls. We recorded An. gambiae mortality and knock-down rates every 15 days during 6 months using standard WHO bioassays.\n\nResultsThe alpha-cypermethrin WG formulation did not last as long as the WP formulation on both surfaces. The difference is higher with the 30mg/m2 concentration for which the WP formulation reached the 80% mortality threshold during 2 months on the mud-plastered walls (3 months on cement) whereas the WG formulation last only one month (2 months on cement).\n\nConclusionsThe new WG formulation has a shorter efficacy than the WHO recommended WP formulation. In this trial, both the WG and WP formulations had low durations of efficacy that would need at least two rounds of spray to cover the entire transmission season.

epidemiology↗