1,721,032 research outputs found
Metabolic reprogramming and gut microbiota ecology drive divergent Plasmodium vivax infection outcomes in Anopheles darlingi.
Full text linkAnopheles darlingi is the principal malaria vector in the Amazon basin, where Plasmodium vivax accounts for the majority of cases. Despite its epidemiological importance, the molecular and microbial determinants of A. darlingi susceptibility to P. vivax remain poorly understood. Here, we investigated vector-parasite-microbiota interactions using experimental infections with field-derived P. vivax gametocytaemic blood, which produced two distinct infection phenotypes: low and high oocyst burdens. Transcriptomic profiling of mosquito midguts across key parasite developmental timepoints revealed that low-infection mosquitoes mounted an early and sustained response characterised by activation of detoxification pathways, redox regulation, aromatic amino acid catabolism, and purine depletion, likely coordinated through neurophysiological cues, which collectively create a metabolically restrictive environment for parasite development. These physiological changes were accompanied by reduced bacterial diversity and enrichment of Enterobacteriales and Pseudomonadales, taxa previously linked to anti-Plasmodium activity. Conversely, high-infection mosquitoes exhibited limited metabolic reprogramming, expansion of Flavobacteriales, and transcriptional signatures consistent with permissive physiological states, potentially associated with reproductive trade-offs. Importantly, low infection outcomes consistently arose from bloodmeals with the lowest gametocyte densities, suggesting that host- and parasite-derived components of the bloodmeal act as early conditioning factors that prime the mosquito midgut for either resistance or susceptibility. These findings reframe A. darlingi vector competence to P. vivax not as a fixed immune trait but as a dynamic outcome of early redox, metabolic, and microbial interactions. They also highlight ecological and physiological targets for transmission-blocking strategies and reinforce the importance of studying vector-parasite interactions in regionally relevant systems
Heterogeneous impacts for malaria control from larviciding across villages and considerations for monitoring and evaluation
Full text linkMalaria vector control tools currently focus on insecticide treated nets (ITNs) and indoor residual spraying in malaria-endemic locations, but additional preventative strategies are needed to address protection gaps. Larval source management (LSM) includes larvicide application to aquatic habitat and an array of alternative forms of environmental efforts. An individual-based transmission model for falciparum malaria is used to demonstrate the theoretical benefit of suppressing malaria adult mosquito vector densities through LSM. The model simulates results of epidemiological trials from Western Kenya (a hilly area with papyrus swamps adjacent to human settlements and moderate to high perennial malaria transmission) and Côte d’Ivoire (an area with Sudanese climate, reducing vegetation cover and high transmission) that applied larvicide alongside ITNs, and investigates whether estimated changes in adult density can be used to project changes in human malaria. In the Western Kenya setting generalised linear models estimate 82% (90% credible intervals: 64% – 92%) and 88% (79% – 94%) reductions in the proportion of adult Anopheles funestus and Anopheles gambiae complex mosquitoes respectively as measured by CDC light traps. In Côte d’Ivoire, an 82% (56% – 93%) reduction of the dominant An. gambiae vector was estimated using standard window trap and pyrethrum spray catch. Both studies had variable village-level impacts. The transmission dynamics model predicted that these entomological impacts would result in a reduction in malaria prevalence in children of 6-months to 10-years of age of 48 – 72% in Kenya, and a 11 – 78% reduction in all-age clinical incidence across villages in Côte d’Ivoire, which are broadly consistent with the empirically observed outcomes. High heterogeneity between villages within the same study indicate that the relative or absolute reductions in mosquito adult density observed in these trials cannot be simply extrapolated to other regions. The LSM strategy adopted, unit area covered, and multiple environmental covariates all contribute to differences in indicators that could be used to assess entomological impacts and the corresponding epidemiological outcomes. This important malaria control tool was impactful across all sites examined, though further work is needed to understand how best to use this tool in the fight against malaria
Manipulation virale et spécificité vectorielle chez les moustiques Anopheles médiés par la protéine G3BP, Rasputin
No full textContrairement aux moustiques Aedes aegypti, vecteurs du virus chikungunya (CHIKV) et de nombreux arbovirus tels que le virus de la dengue et le virus Zika, les moustiques Anopheles gambiae sont les vecteurs du parasite Plasmodium, agent causal du paludisme. La réponse des agents pathogènes chez les anophèles a été très étudiée pour Plasmodium en raison de l'importance clinique de cet agent pathogène dans le monde. Le seul arbovirus connu activement transmis par ces moustiques est o'nyong-nyong (ONNV). Le potentiel vectoriel des anophèles pour la transmission virale est peu connu. Cependant, la présence d’arbovirus chez ces moustiques indique une possibilité pour les anophèles de devenir des vecteurs viraux plus importants à l'avenir. La réponse antivirale chez ces moustiques a été principalement étudiée avec ONNV, bien que peu d'information soit disponible sur le sujet. Les « Ras-GAP SH3 domain-binding protein » (G3BP) et leur orthologue, Rasputin, chez le moustique ont été très étudiés chez les mammifères et seulement explorés chez les moustiques Aedes en tant que facteurs proviraux. Cependant, le rôle de Rasputin chez les anophèles et le mécanisme moléculaire proviral exact médié par Rasputin et les G3BPs n’est pas connu. Par conséquent, le premier objectif de cette thèse est d'évaluer le rôle de Rasputin lors de l'infection de ONNV chez les moustiques anophèles en se concentrant sur la modulation de l’immunité antivirale. En utilisant une combinaison de méthodes génomiques, microscopiques et biochimiques, j'ai prouvé, pour la première fois, que Rasputin agit via un nouveau mécanisme de détournement viral médié par son interaction avec la protéine virale non structurale 3 (nsP3) de ONNV. Rasputin agit comme l’interrupteur entre une immunité stérile et une infection virale au cours de la première phase d'infection de l’abdomen chez les moustiques.La deuxième partie de mon projet de thèse se concentre sur les facteurs déterminants la spécificité vectorielle chez les moustiques en utilisant ONNV et CHIKV comme modèle expérimental. ONNV et CHIKV sont deux alphavirus étroitement apparentés avec de nombreuses similitudes dans leur biologie, la seule différence connue entre ces deux virus est leur transmission par deux genres de moustiques différents. Des études ont révélé que nsP3 pourrait être un déterminant de la spécificité vectorielle entre ces deux virus, par conséquent nous évaluons le rôle de l'interaction entre Rasputin et nsP3 dans ce processus. En utilisant différentes méthodes génomiques et cellulaires, j'ai mis en évidence que Rasputin agit comme facteur proviral de CHIKV chez les anophèles. J'ai également montré que l'interaction entre Rasputin et nsP3 est en partie dépendant de l’origine virale du domaine hypervariable de nsP3. J’ai pu mettre en évidence que cette interaction pourrait jouer un rôle, au moins partiel, dans la spécificité vectorielle. Enfin, j'ai étudié le rôle d'un nouveau facteur impliqué dans l'infection de ONNV codé par le gène AGAP000570. J'ai montré que ce facteur extracellulaire a un rôle proviral au cours de l'infection d’ONNV via un possible mécanisme paracrine. J'ai également étudié la relation entre ce facteur proviral et Rasputin lors d'une infection virale révélant que ces deux protéines pourraient agir dans la même voie et qu’elles peuvent réguler leurs expressions transcriptionnelles entre elles. Ces résultats génèrent de nouvelles informations biologiques sur la fonction provirale de Rasputin dans la manipulation des voies immunitaires antivirales chez les moustiques qui pourraient être étendues au rôle de l'orthologue G3BP chez les mammifères.Aedes aegypti mosquitoes are vectors of many arboviruses including chikungunya virus (CHIKV), Dengue virus, yellow fever virus, and Zika virus. In contrast Anopheles gambiae transmit the parasite Plasmodium, causative agent of malaria. The response of Anopheles mosquitoes to pathogens has been studied mainly for Plasmodium due to the clinical importance of malaria. The only known arbovirus for which Anopheles is the primary vector is o’nyong-nyong virus (ONNV). It is not understood why Anopheles apparently do not display more vectorial potential for arboviruses, particularly because the presence of a virome and transmission of ONNV suggests a potential risk for Anopheles to become a more prominent arbovirus vector in the future. Antiviral response in Anopheles has primarily been studied using ONNV, although only relatively few reports have been published on the subject. The mosquito orthologs of Ras-GAP SH3 domain binding proteins (G3BP), called Rasputin, has been studied in mammals but barely examined in mosquitoes where Rasputin was shown to act as a proviral factor in Aedes, but the proviral molecular mechanism is not understood yet. The first objective of this thesis is to assess the role of Rasputin during ONNV infection in Anopheles mosquitoes and to determine the mechanism mediated by Rasputin. We hypothesis that Rasputin may interact with host antiviral immunity. By using a combination of genomic, cellular, and biochemical methods, I provide evidence that Rasputin is proviral because of the viral manipulation of Rasputin to modulate antiviral immune signaling pathways. These results indicate, for the first time, that Rasputin is required for viral hijacking as a physical target of the viral non-structural protein 3 (nsP3) of ONNV. The second part of my thesis project focused on vectorial specificity in mosquitoes by using the comparison of two closely related alphaviruses, ONNV and CHIKV, as an experimental model. ONNV and CHIKV display many similarities in their biology and pathology, with the major difference being their use of vector species (Anopheles and Aedes, respectively). Previous evidence suggested that nsP3 could be a determinant of vectorial specificity between those two viruses, and here we hypothesize that the role of the interaction between Rasputin and nsP3 of the two different viruses and mosquitoes has a role in vector specificity. By using genomic and cellular methods, I highlighted that Rasputin also acts as a proviral factor for CHIKV in an Anopheles cellular model. Moreover, we found that the match between Anopheles or Aedes Rasputin and the nsP3 of each virus is an important determinant of the cell-specific viral infection. Thus, the interaction between Rasputin and nsP3 of CHIKV and ONNV at least in part influences vectorial specificity for these alphaviruses. Finally, I studied the role of a new host factor involved in ONNV infection of Anopheles encoded by the gene AGAP000570. I characterized the proviral role of this extracellular factor during ONNV infection through a possible paracrine-like mechanism. I also assess the relationship between this secreted factor and Rasputin during viral infection and revealed that those two proteins could act in the same functional pathway. These results generate novel biological insight for the proviral function of Rasputin in manipulating antiviral immune pathways in mosquitoes that could be extended to the role of G3BP in mammals
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Dietary cholesterol modulates pathogen blocking by Wolbachia
Full text linkThe bacterial endosymbiont Wolbachia pipientis protects its hosts from a range of pathogens by limiting their ability to form infections inside the insect. This "pathogen blocking" could be explained by innate immune priming by the symbiont, competition for host-derived resources between pathogens and Wolbachia, or the direct modification of the cell or cellular environment by Wolbachia. Recent comparative work in Drosophila and the mosquito Aedes aegypti has shown that an immune response is not required for pathogen blocking, implying that there must be an additional component to the mechanism. Here we have examined the involvement of cholesterol in pathogen blocking using a system of dietary manipulation in Drosophila melanogaster in combination with challenge by Drosophila C virus (DCV), a common fly pathogen. We observed that flies reared on cholesterol-enriched diets infected with the Wolbachia strains wMelPop and wMelCS exhibited reduced pathogen blocking, with viral-induced mortality occurring 2-5 days earlier than flies reared on Standard diet. This shift toward greater virulence in the presence of cholesterol also corresponded to higher viral copy numbers in the host. Interestingly, an increase in dietary cholesterol did not have an effect on Wolbachia density except in one case, but this did not directly affect the strength of pathogen blocking. Our results indicate that host cholesterol levels are involved with the ability of Wolbachia-infected flies to resist DCV infections, suggesting that cholesterol contributes to the underlying mechanism of pathogen blocking
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Anopheles coluzzii stearoyl-CoA desaturase is essential for adult female survival and reproduction upon blood feeding.
Full text linkVitellogenesis and oocyte maturation require anautogenous female Anopheles mosquitoes to obtain a bloodmeal from a vertebrate host. The bloodmeal is rich in proteins that are readily broken down into amino acids in the midgut lumen and absorbed by the midgut epithelial cells where they are converted into lipids and then transported to other tissues including ovaries. The stearoyl-CoA desaturase (SCD) plays a pivotal role in this process by converting saturated (SFAs) to unsaturated (UFAs) fatty acids; the latter being essential for maintaining cell membrane fluidity amongst other housekeeping functions. Here, we report the functional and phenotypic characterization of SCD1 in the malaria vector mosquito Anopheles coluzzii. We show that RNA interference (RNAi) silencing of SCD1 and administration of sterculic acid (SA), a small molecule inhibitor of SCD1, significantly impact on the survival and reproduction of female mosquitoes following blood feeding. Microscopic observations reveal that the mosquito thorax is quickly filled with blood, a phenomenon likely caused by the collapse of midgut epithelial cell membranes, and that epithelial cells are depleted of lipid droplets and oocytes fail to mature. Transcriptional profiling shows that genes involved in protein, lipid and carbohydrate metabolism and immunity-related genes are the most affected by SCD1 knock down (KD) in blood-fed mosquitoes. Metabolic profiling reveals that these mosquitoes exhibit increased amounts of saturated fatty acids and TCA cycle intermediates, highlighting the biochemical framework by which the SCD1 KD phenotype manifests as a result of a detrimental metabolic syndrome. Accumulation of SFAs is also the likely cause of the potent immune response observed in the absence of infection, which resembles an auto-inflammatory condition. These data provide insights into mosquito bloodmeal metabolism and lipid homeostasis and could inform efforts to develop novel interventions against mosquito-borne diseases
Wolbachia stimulates immune gene expression and inhibits Plasmodium development in Anopheles gambia
Full text linkThe over-replicating wMelPop strain of the endosymbiont Wolbachia pipientis has recently been shown to be capable of inducing immune upregulation and inhibition of pathogen transmission in Aedes aegypti mosquitoes. In order to examine whether comparable effects would be seen in the malaria vector Anopheles gambiae, transient somatic infections of wMelPop were created by intrathoracic inoculation. Upregulation of six selected immune genes was observed compared to controls, at least two of which (LRIM1 and TEP1) influence the development of malaria parasites. A stably infected An. gambiae cell line also showed increased expression of malaria-related immune genes. Highly significant reductions in Plasmodium infection intensity were observed in the wMelPop-infected cohort, and using gene knockdown, evidence for the role of TEP1 in this phenotype was obtained. Comparing the levels of upregulation in somatic and stably inherited wMelPop infections in Ae. aegypti revealed that levels of upregulation were lower in the somatic infections than in the stably transinfected line; inhibition of development of Brugia filarial nematodes was nevertheless observed in the somatic wMelPop infected females. Thus we consider that the effects observed in An. gambiae are also likely to be more pronounced if stably inherited wMelPop transinfections can be created, and that somatic infections of Wolbachia provide a useful model for examining effects on pathogen development or dissemination. The data are discussed with respect to the comparative effects on malaria vectorial capacity of life shortening and direct inhibition of Plasmodium development that can be produced by Wolbachia
Existing Infection Facilitates Establishment and Density of Malaria Parasites in Their Mosquito Vector
Full text linkVery little is known about how vector-borne pathogens interact within their vector and how this impacts transmission. Here we show that mosquitoes can accumulate mixed strain malaria infections after feeding on multiple hosts. We found that parasites have a greater chance of establishing and reach higher densities if another strain is already present in a mosquito. Mixed infections contained more parasites but these larger populations did not have a detectable impact on vector survival. Together these results suggest that mosquitoes taking multiple infective bites may disproportionally contribute to malaria transmission. This will increase rates of mixed infections in vertebrate hosts, with implications for the evolution of parasite virulence and the spread of drug-resistant strains. Moreover, control measures that reduce parasite prevalence in vertebrate hosts will reduce the likelihood of mosquitoes taking multiple infective feeds, and thus disproportionally reduce transmission. More generally, our study shows that the types of strain interactions detected in vertebrate hosts cannot necessarily be extrapolated to vectors.</p
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