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1.
Nat Commun ; 12(1): 2290, 2021 04 16.
Article in English | MEDLINE | ID: mdl-33863888

ABSTRACT

Arthropod-borne viruses pose a major threat to global public health. Thus, innovative strategies for their control and prevention are urgently needed. Here, we exploit the natural capacity of viruses to generate defective viral genomes (DVGs) to their detriment. While DVGs have been described for most viruses, identifying which, if any, can be used as therapeutic agents remains a challenge. We present a combined experimental evolution and computational approach to triage DVG sequence space and pinpoint the fittest deletions, using Zika virus as an arbovirus model. This approach identifies fit DVGs that optimally interfere with wild-type virus infection. We show that the most fit DVGs conserve the open reading frame to maintain the translation of the remaining non-structural proteins, a characteristic that is fundamental across the flavivirus genus. Finally, we demonstrate that the high fitness DVG is antiviral in vivo both in the mammalian host and the mosquito vector, reducing transmission in the latter by up to 90%. Our approach establishes the method to interrogate the DVG fitness landscape, and enables the systematic identification of DVGs that show promise as human therapeutics and vector control strategies to mitigate arbovirus transmission and disease.


Subject(s)
Antiviral Agents/administration & dosage , Defective Viruses/genetics , Mosquito Vectors/drug effects , Zika Virus Infection/drug therapy , Zika Virus/genetics , Aedes/drug effects , Aedes/virology , Animals , Chlorocebus aethiops , Computational Biology , Directed Molecular Evolution , Disease Models, Animal , Female , Genetic Fitness , Genome, Viral/genetics , HEK293 Cells , Humans , Mice , Mosquito Control/methods , Mosquito Vectors/virology , Open Reading Frames/genetics , RNA, Viral/genetics , Vero Cells , Zika Virus Infection/transmission , Zika Virus Infection/virology
2.
Mem Inst Oswaldo Cruz ; 115: e200313, 2021.
Article in English | MEDLINE | ID: mdl-33533870

ABSTRACT

BACKGROUND: Aedes aegypti is the sole vector of urban arboviruses in French Guiana. Overtime, the species has been responsible for the transmission of viruses during yellow fever, dengue, chikungunya and Zika outbreaks. Decades of vector control have produced resistant populations to deltamethrin, the sole molecule available to control adult mosquitoes in this French Territory. OBJECTIVES: Our surveillance aimed to provide public health authorities with data on insecticide resistance in Ae. aegypti populations and other species of interest in French Guiana. Monitoring resistance to the insecticide used for vector control and to other molecule is a key component to develop an insecticide resistance management plan. METHODS: In 2009, we started to monitor resistance phenotypes to deltamethrin and target-site mechanisms in Ae. aegypti populations across the territory using the WHO impregnated paper test and allelic discrimination assay. FINDINGS: Eight years surveillance revealed well-installed resistance and the dramatic increase of alleles on the sodium voltage-gated gene, known to confer resistance to pyrethroids (PY). In addition, we observed that populations were resistant to malathion (organophosphorous, OP) and alpha-cypermethrin (PY). Some resistance was also detected to molecules from the carbamate family. Finally, those populations somehow recovered susceptibility against fenitrothion (OP). In addition, other species distributed in urban areas revealed to be also resistant to pyrethroids. CONCLUSION: The resistance level can jeopardize the efficiency of chemical adult control in absence of other alternatives and conducts to strongly rely on larval control measures to reduce mosquito burden. Vector control strategies need to evolve to maintain or regain efficacy during epidemics.


Subject(s)
Aedes/drug effects , Insect Vectors/genetics , Insecticide Resistance/genetics , Insecticides/pharmacology , Mosquito Vectors/drug effects , Pyrethrins/pharmacology , Aedes/genetics , Aedes/virology , Animals , French Guiana , Insect Vectors/drug effects , Mosquito Control/methods , Mosquito Vectors/virology , Spatio-Temporal Analysis
3.
PLoS One ; 16(1): e0244284, 2021.
Article in English | MEDLINE | ID: mdl-33417600

ABSTRACT

BACKGROUND: Mosquito-borne diseases remain a significant public health problem in tropical regions. Housing improvements such as screening of doors and windows may be effective in reducing disease transmission, but the impact remains unclear. OBJECTIVES: To examine whether housing interventions were effective in reducing mosquito densities in homes and the impact on the incidence of mosquito-borne diseases. METHODS: In this systematic review and meta-analysis, we searched 16 online databases, including NIH PubMed, CINAHL Complete, LILACS, Ovid MEDLINE, and Cochrane Central Register of Controlled Trials for randomized trials published from database inception to June 30, 2020. The primary outcome was the incidence of any mosquito-borne diseases. Secondary outcomes encompassed entomological indicators of the disease transmission. I2 values were used to explore heterogeneity between studies. A random-effects meta-analysis was used to assess the primary and secondary outcomes, with sub-group analyses for type of interventions on home environment, study settings (rural, urban, or mixed), and overall house type (traditional or modern housing). RESULTS: The literature search yielded 4,869 articles. After screening, 18 studies were included in the qualitative review, of which nine were included in the meta-analysis. The studies enrolled 7,200 households in Africa and South America, reporting on malaria or dengue only. The type of home environmental interventions included modification to ceilings and ribbons to close eaves, screening doors and windows with nets, insecticide-treated wall linings in homes, nettings over gables and eaves openings, mosquito trapping systems, metal-roofed houses with mosquito screening, gable windows and closed eaves, and prototype houses using southeast Asian designs. Pooled analysis depicted a lower risk of mosquito-borne diseases in the housing intervention group (OR = 0.68; 95% CI = 0.48 to 0.95; P = 0.03). Subgroup analysis depicted housing intervention reduced the risk of malaria in all settings (OR = 0.63; 95% CI = 0.39 to 1.01; P = 0.05). In urban environment, housing intervention was found to decrease the risk of both malaria and dengue infections (OR = 0.52; 95% CI = 0.27 to 0.99; P = 0.05).Meta-analysis of pooled odds ratio showed a significant benefit of improved housing in reducing indoor vector densities of both Aedes and Anopheles (OR = 0.35; 95% CI = 0.23 to 0.54; P<0.001). CONCLUSIONS: Housing intervention could reduce transmission of malaria and dengue among people living in the homes. Future research should evaluate the protective effect of specific house features and housing improvements associated with urban development.


Subject(s)
Housing , Malaria/prevention & control , Mosquito Control/methods , Vector Borne Diseases/prevention & control , Aedes/drug effects , Aedes/physiology , Animals , Humans , Insecticides/pharmacology , Malaria/transmission , Odds Ratio , Risk Factors , Vector Borne Diseases/transmission
4.
PLoS One ; 16(1): e0243992, 2021.
Article in English | MEDLINE | ID: mdl-33428654

ABSTRACT

Insecticide resistance is a worldwide threat for vector control around the world, and Aedes aegypti, the main vector of several arboviruses, is a particular concern. To better understand the mechanisms of resistance, four isofemale strains originally from French Guiana were isolated and analysed using combined approaches. The activity of detoxification enzymes involved in insecticide resistance was assayed, and mutations located at positions 1016 and 1534 of the sodium voltage-gated channel gene, which have been associated with pyrethroid resistance in Aedes aegypti populations in Latin America, were monitored. Resistance to other insecticide families (organophosphates and carbamates) was evaluated. A large-scale proteomic analysis was performed to identify proteins involved in insecticide resistance. Our results revealed a metabolic resistance and resistance associated with a mutation of the sodium voltage-gated channel gene at position 1016. Metabolic resistance was mediated through an increase of esterase activity in most strains but also through the shifts in the abundance of several cytochrome P450 (CYP450s). Overall, resistance to deltamethrin was linked in the isofemale strains to resistance to other class of insecticides, suggesting that cross- and multiple resistance occur through selection of mechanisms of metabolic resistance. These results give some insights into resistance to deltamethrin and into multiple resistance phenomena in populations of Ae. aegypti.


Subject(s)
Aedes/metabolism , Cytochrome P-450 Enzyme System/genetics , Insect Proteins/genetics , Insecticide Resistance/genetics , Voltage-Gated Sodium Channels/genetics , Aedes/drug effects , Aedes/genetics , Animals , Esterases/metabolism , Female , French Guiana , Gene Knockdown Techniques , Genotype , Inactivation, Metabolic/genetics , Insect Proteins/antagonists & inhibitors , Insect Proteins/metabolism , Insecticides/pharmacology , Intestinal Mucosa/metabolism , Nitriles/pharmacology , Oligonucleotides/metabolism , Polymorphism, Single Nucleotide , Proteome/analysis , Proteomics , Pyrethrins/pharmacology , Voltage-Gated Sodium Channels/chemistry , Voltage-Gated Sodium Channels/metabolism
5.
Parasit Vectors ; 14(1): 9, 2021 Jan 06.
Article in English | MEDLINE | ID: mdl-33407825

ABSTRACT

BACKGROUND: With widespread insecticide resistance in mosquito vectors, there is a pressing need to evaluate alternatives with different modes of action. Blood containing the antihelminthic drug ivermectin has been shown to have lethal and sub-lethal effects on mosquitoes. Almost all work to date has been on Anopheles spp., but impacts on other anthropophagic vectors could provide new options for their control, or additional value to anti-malarial ivermectin programmes. METHODS: Using dose-response assays, we evaluated the effects of ivermectin delivered by membrane feeding on daily mortality (up to 14 days post-blood feed) and fecundity of an Indian strain of Aedes aegypti. RESULTS: The 7-day lethal concentration of ivermectin required to kill 50% of adult mosquitoes was calculated to be 178.6 ng/ml (95% confidence intervals 142.3-218.4) for Ae. aegypti, which is much higher than that recorded for Anopheles spp. in any previous study. In addition, significant effects on fecundity and egg hatch rates were only recorded at high ivermectin concentrations (≥ 250 ng/ul). CONCLUSION: Our results suggest that levels of ivermectin present in human blood at current dosing regimes in mass drug administration campaigns, or even those in a recent higher-dose anti-malaria trial, are unlikely to have a substantial impact on Ae. aegypti. Moreover, owing to the strong anthropophagy of Ae. aegypti, delivery of higher levels of ivermectin in livestock blood is also unlikely to be an effective option for its control. However, other potential toxic impacts of ivermectin metabolites, accumulation in tissues, sublethal effects on behaviour, or antiviral action might increase the efficacy of ivermectin against Ae. aegypti and the arboviral diseases it transmits, and require further investigation.


Subject(s)
Aedes/drug effects , Arbovirus Infections/prevention & control , Ivermectin/pharmacology , Animals , Anthelmintics/administration & dosage , Anthelmintics/pharmacology , Arbovirus Infections/transmission , Fertility/drug effects , Ivermectin/administration & dosage , Mortality , Mosquito Control/methods , Mosquito Vectors/drug effects
6.
PLoS Pathog ; 17(1): e1009199, 2021 01.
Article in English | MEDLINE | ID: mdl-33465145

ABSTRACT

The insecticidal Cry11Aa and Cyt1Aa proteins are produced by Bacillus thuringiensis as crystal inclusions. They work synergistically inducing high toxicity against mosquito larvae. It was proposed that these crystal inclusions are rapidly solubilized and activated in the gut lumen, followed by pore formation in midgut cells killing the larvae. In addition, Cyt1Aa functions as a Cry11Aa binding receptor, inducing Cry11Aa oligomerization and membrane insertion. Here, we used fluorescent labeled crystals, protoxins or activated toxins for in vivo localization at nano-scale resolution. We show that after larvae were fed solubilized proteins, these proteins were not accumulated inside the gut and larvae were not killed. In contrast, if larvae were fed soluble non-toxic mutant proteins, these proteins were found inside the gut bound to gut-microvilli. Only feeding with crystal inclusions resulted in high larval mortality, suggesting that they have a role for an optimal intoxication process. At the macroscopic level, Cry11Aa completely degraded the gastric caeca structure and, in the presence of Cyt1Aa, this effect was observed at lower toxin-concentrations and at shorter periods. The labeled Cry11Aa crystal protein, after midgut processing, binds to the gastric caeca and posterior midgut regions, and also to anterior and medium regions where it is internalized in ordered "net like" structures, leading finally to cell break down. During synergism both Cry11Aa and Cyt1Aa toxins showed a dynamic layered array at the surface of apical microvilli, where Cry11Aa is localized in the lower layer closer to the cell cytoplasm, and Cyt1Aa is layered over Cry11Aa. This array depends on the pore formation activity of Cry11Aa, since the non-toxic mutant Cry11Aa-E97A, which is unable to oligomerize, inverted this array. Internalization of Cry11Aa was also observed during synergism. These data indicate that the mechanism of action of Cry11Aa is more complex than previously anticipated, and may involve additional steps besides pore-formation activity.


Subject(s)
Aedes/drug effects , Drug Synergism , Endotoxins/metabolism , Gastrointestinal Tract/drug effects , Hemolysin Proteins/metabolism , Insecticides/metabolism , Larva/drug effects , Aedes/metabolism , Animals , /toxicity , Bacterial Proteins , Endotoxins/genetics , Endotoxins/toxicity , Gastrointestinal Tract/metabolism , Hemolysin Proteins/genetics , Hemolysin Proteins/toxicity , Insecticides/toxicity , Larva/metabolism , Protein Binding
7.
J Agric Food Chem ; 69(3): 1091-1106, 2021 Jan 27.
Article in English | MEDLINE | ID: mdl-33432806

ABSTRACT

Furanocoumarins are photoactive compounds derived from secondary plant metabolites. They possess many bioactivities, including antioxidative, anticancer, insecticidal, and bactericidal activities. Here, we designed a new scheme for synthesizing 2-arylfuranocoumarin derivatives by condensation, esterification, bromination, and Wittig reaction. We found that 2-thiophenylfuranocoumarin (Iy) had excellent photosensitive activity. Three Iy concentrations (LC25, LC50, and LC75) were used to treat the fourth instar larvae of Aedes aegypti (A. aegypti). The photoactivated toxicity, sublethal dose, mitochondrial dysfunction, oxidative stress level, intestinal barrier dysfunction, and apoptosis were studied. The results showed that Iy induced reactive oxygen species (ROS) production in midgut cells under ultraviolet light. Ultrastructural analysis demonstrated that mitochondria were damaged, and the activities of related enzymes were inhibited. Ultimately, Iy exposure led to excessive ROS production followed by the inhibition of antioxidant enzymes, including SOD, CAT, GPx, and GR, which diminished ROS elimination and escalated oxidative stress in midgut cells, aggravating the degree of oxidative damage in these cells. Histopathological changes were observed in the midgut, which led to intestinal barrier dysfunction. When the elimination of ROS was blocked and it accumulated in cells, apoptosis-related genes, including AeDronc, AeCaspase7, and AeCaspase8, were induced and activated. In addition, Iy affected the growth and development of A. aegypti at sublethal concentrations, and there was an obvious post-lethal effect. Thus, we found that Iy caused midgut damage and apoptosis in A. aegypti larvae under ultraviolet light, which preliminarily revealed the mode of action of Iy in A. aegypti.


Subject(s)
Aedes/drug effects , Apoptosis/drug effects , Furocoumarins/chemistry , Furocoumarins/toxicity , Insecticides/chemical synthesis , Insecticides/toxicity , Aedes/physiology , Animals , Digestive System/drug effects , Digestive System/metabolism , Insecticides/chemistry , Larva/drug effects , Larva/physiology , Mitochondria/drug effects , Mitochondria/metabolism , Reactive Oxygen Species/metabolism
8.
Viruses ; 13(1)2021 Jan 14.
Article in English | MEDLINE | ID: mdl-33466915

ABSTRACT

Mosquito-borne arthropod-borne viruses (arboviruses) such as the dengue virus (DENV), Zika virus (ZIKV), and chikungunya virus (CHIKV) are important human pathogens that are responsible for significant global morbidity and mortality. The recent emergence and re-emergence of mosquito-borne viral diseases (MBVDs) highlight the urgent need for safe and effective vaccines, therapeutics, and vector-control approaches to prevent MBVD outbreaks. In nature, arboviruses circulate between vertebrate hosts and arthropod vectors; therefore, disrupting the virus lifecycle in mosquitoes is a major approach for combating MBVDs. Several strategies were proposed to render mosquitoes that are refractory to arboviral infection, for example, those involving the generation of genetically modified mosquitoes or infection with the symbiotic bacterium Wolbachia. Due to the recent development of high-throughput screening methods, an increasing number of drugs with inhibitory effects on mosquito-borne arboviruses in mammalian cells were identified. These antivirals are useful resources that can impede the circulation of arboviruses between arthropods and humans by either rendering viruses more vulnerable in humans or suppressing viral infection by reducing the expression of host factors in mosquitoes. In this review, we summarize recent advances in small-molecule antiarboviral drugs in mammalian and mosquito cells, and discuss how to use these antivirals to block the transmission of MBVDs.


Subject(s)
Aedes/virology , Antiviral Agents/pharmacology , Arbovirus Infections/transmission , Arbovirus Infections/virology , Arboviruses/drug effects , Mosquito Vectors/virology , Aedes/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Arbovirus Infections/drug therapy , Arboviruses/classification , Cells, Cultured , Drug Discovery/methods , Drug Evaluation, Preclinical , Humans , Mosquito Control/methods , Vector Borne Diseases/drug therapy , Vector Borne Diseases/transmission , Vector Borne Diseases/virology , Virus Replication/drug effects
9.
Mem Inst Oswaldo Cruz ; 115: e200271, 2020.
Article in English | MEDLINE | ID: mdl-33146241

ABSTRACT

BACKGROUND: Aedes aegypti is the primary transmitter of several arbovirus with great impact in human health. Controlling vector mosquitoes is an essential and complex task. One promising control method is to use mosquitoes as a vehicle to disseminate tiny particles of juvenile-killing insecticides, such as pyriproxyfen (PPF), to breeding sites. OBJECTIVES: We aimed to investigate the capacity of Ae. aegypti to disseminate two new formulations of PPF in two sites of Rio de Janeiro city for assessment of the efficacy of these products. METHODS: Dissemination stations impregnated with powder and liquid new formulations of PPF were installed in two test sites. Ovitraps were used in the test sites and in a control site for monitoring the presence of Ae. aegypti throughout eggs collection. FINDINGS: Entomological indices indicated that the new formulations of PPF were efficient in reducing eggs abundance. Liquid formulation performed better than powder formulation. Ready-to-use formulations of PPF can be quickly applied in the field and can be replaced after a few months. MAIN CONCLUSIONS: New formulations of PPF associated with mosquito dissemination approach make a valuable vector control strategy, managing to cover places of difficult access for whatever reason. New formulations application requires less labour, being economically attractive.


Subject(s)
Aedes/drug effects , Insecticides/pharmacology , Larva/drug effects , Mosquito Control/methods , Pyridines/pharmacology , Adolescent , Animals , Cities , Humans , Larva/growth & development , Mosquito Vectors/drug effects , Mosquito Vectors/growth & development
10.
PLoS One ; 15(10): e0228695, 2020.
Article in English | MEDLINE | ID: mdl-33022007

ABSTRACT

Aedes aegypti is the main vector of dengue, chikungunya, and Zika viruses, which are of great public health importance in Colombia. Aedes control strategies in Colombia rely heavily on the use of organophosphate and pyrethroid insecticides, providing constant selection pressure and the emergence of resistant populations. In recent years, insecticide use has increased due to the increased incidence of dengue and recent introductions of chikungunya and Zika. In the present study, pyrethroid resistance was studied across six populations of Ae. aegypti from the Caribbean coast of Colombia. Susceptibility to λ-cyhalothrin, deltamethrin, and permethrin was assessed, and resistance intensity was determined. Activity levels of enzymes associated with resistance were measured, and the frequencies of three kdr alleles (V1016I, F1534C, V410L) were calculated. Results showed variations in pyrethroid susceptibility across Ae. aegypti populations and altered enzyme activity levels were detected. The kdr alleles were detected in all populations, with high variations in frequencies: V1016I (frequency ranging from 0.15-0.70), F1534C (range 0.94-1.00), and V410L (range 0.05-0.72). In assays of phenotyped individuals, associations were observed between the presence of V1016I, F1534C, and V410L alleles and resistance to the evaluated pyrethroids, as well as between the VI1016/CC1534/VL410 tri-locus genotype and λ-cyhalothrin and permethrin resistance. The results of the present study contribute to the knowledge of the mechanisms underlying the resistance to key pyrethroids used to control Ae. aegypti along the Caribbean coast of Colombia.


Subject(s)
Aedes/genetics , Insecticide Resistance , Mutation , Pyrethrins/pharmacology , Vascular Endothelial Growth Factor Receptor-2/genetics , Aedes/drug effects , Animals , Colombia , Gene Frequency , Insect Proteins/genetics , Male , Nitriles/pharmacology , Permethrin/pharmacology , Phenotype
11.
Pestic Biochem Physiol ; 170: 104686, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32980070

ABSTRACT

New insecticides are urgently needed for the control of arthropod vectors of public health diseases. As resistance to many insecticides used for the control of public health pests is ubiquitous, all available chemistries should be evaluated for their potential to effectively control both insecticide-susceptible and insecticide-resistant strains of mosquitoes. This study aimed to evaluate p-p'-difluoro-diphenyl-trichloroethane (DFDT) as a mosquito control technology and relate its activity to that of DDT. We found that topical DFDT was significantly less toxic than DDT to both pyrethroid-susceptible and pyrethroid-resistant strains of Anopheles gambiae and Aedes aegypti. Direct nervous system recording from Drosophila melanogaster CNS demonstrated that DFDT is approximately 10-times less potent than DDT at blocking nerve firing, which may explain its relatively lower toxicity. DFDT was shown to be at least 4500 times more vapor-active than DDT, with an LC50 in a vapor toxicity screening assay of 2.2 µg/cm2. Resistance to DFDT was assessed in two mosquito strains that possess target-site mutations in the voltage-gated sodium channel and upregulated metabolic activity. Resistance ratios for Akdr (An. gambiae) and Puerto Rico (Ae. aegypti) strains were 9.2 and 12.2, respectively. Overall, this study demonstrates that DFDT is unlikely to be a viable public health vector control insecticide.


Subject(s)
Aedes/drug effects , Insecticides/pharmacology , Insecticides/toxicity , Pyrethrins/toxicity , Animals , Biphenyl Compounds , DDT/toxicity , Drosophila melanogaster/drug effects , Drosophila melanogaster/genetics , Insecticide Resistance/drug effects , Mosquito Vectors , Puerto Rico , Trichloroethanes
12.
Pestic Biochem Physiol ; 170: 104666, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32980073

ABSTRACT

Despite the substantial progress achieved in the characterization of cytochrome P450 (CYP) -based resistance mechanisms in mosquitoes, a number of questions remain unanswered. These include: (i) the regulation and physiology of resistance conferring CYPs; (ii) the actual contribution of CYPs in resistance alone or in combination with other detoxification partners or other resistance mechanisms; (iii) the association between overexpression levels and allelic variation, with the catalytic activity and the intensity of resistance and (iv) the true value of molecular diagnostics targeting CYP markers, for driving decision making in the frame of Insecticide Resistance Management applications. Furthermore, the translation of CYP - based insecticide resistance research in mosquitoes into practical applications, is being developed, but it is not fully exploited, as yet. Examples include the production of high throughput platforms for screening the liability (stability) or inhibition potential of novel insecticidal leads and synergists (add-ons), as well as the exploration of the negative cross resistance concept (i.e. detoxification of certain insecticides, but activation of others pro-insecticides). The goal of this review is to critically summarise the current knowledge and the gaps of the CYP-based metabolic insecticide resistance in Anopheles and Aedes mosquito vectors. The progress and limitations of the protein and the reverse/forward genetic approaches, the understanding and importance of molecular and physiological aspects, as well as the current and future exploitation routes of CYP research are discussed.


Subject(s)
Aedes/drug effects , Aedes/genetics , Anopheles/drug effects , Anopheles/genetics , Insecticides/pharmacology , Pyrethrins , Animals , Cytochrome P-450 Enzyme System/genetics , Insecticide Resistance/drug effects , Insecticide Resistance/genetics , Mosquito Vectors/genetics
13.
PLoS Negl Trop Dis ; 14(9): e0008654, 2020 09.
Article in English | MEDLINE | ID: mdl-32976503

ABSTRACT

Effectively controlling vector mosquito populations while avoiding the development of resistance remains a prevalent and increasing obstacle to integrated vector management. Although, metallic nanoparticles have previously shown promise in controlling larval populations via mechanisms which are less likely to spur resistance, the impacts of such particles on life history traits and fecundity of mosquitoes are understudied. Herein, we investigate the chemically well-defined cerium oxide nanoparticles (CNPs) and silver-doped nanoceria (AgCNPs) for larvicidal potential and effects on life history traits and fecundity of Aedes (Ae.) aegypti mosquitoes. When 3rd instar larvae were exposed to nanoceria in absence of larval food, the mortality count disclosed significant activity of AgCNPs over CNPs (57.8±3.68% and 17.2±2.81% lethality, respectively) and a comparable activity to Ag+ controls (62.8±3.60% lethality). The surviving larvae showed altered life history traits (e.g., reduced egg hatch proportion and varied sex ratios), indicating activities of these nanoceria beyond just that of a larvicide. In a separate set of experiments, impacts on oocyte growth and egg generation resulting from nanoceria-laced blood meals were studied using confocal fluorescence microscopy revealing oocytes growth-arrest at 16-24h after feeding with AgCNP-blood meals in some mosquitoes, thereby significantly reducing average egg clutch. AgCNPs caused ~60% mortality in 3rd instar larvae when larval food was absent, while CNPs yielded only ~20% mortality which contrasts with a previous report on green-synthesized nanoceria and highlights the level of detail required to accurately report and interpret such studies. Additionally, AgCNPs are estimated to contain much less silver (0.22 parts per billion, ppb) than the amount of Ag+ needed to achieve comparable larvicidal activity (2.7 parts per million, ppm), potentially making these nanoceria ecofriendly. Finally, this work is the first study to demonstrate the until-now-unappreciated impacts of nanoceria on life history traits and interference with mosquito egg development.


Subject(s)
Aedes/drug effects , Cerium/pharmacology , Fertility/drug effects , Larva/drug effects , Life History Traits , Animals , Female , Metal Nanoparticles/chemistry , Mosquito Control/methods , Particle Size , Silver/pharmacology
14.
SAR QSAR Environ Res ; 31(10): 717-739, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32930630

ABSTRACT

Aedes aegypti is the primary vector of several infectious viruses that cause yellow, dengue, chikungunya, and Zika fevers. Recently, plant-derived products have been tested as safe and eco-friendly larvicides against Ae. aegypti. The present study aimed to improve QSAR models for 62 larvicidal phytocompounds against Ae. aegypti via the Monte Carlo method based on the index of the ideality of correlation (IIC) criterion. The representation of structures was done with SMILES. Three splits were prepared randomly and three QSAR models were constructed using IIC target function. The molecular descriptors were selected from SMILES descriptors and the hydrogen-filled molecular graphs. The predictability of three models was evaluated on the validation sets, the r 2 of which was 0.9770, 0.8660, and 0.8565 for models 1 to 3, respectively. The statistical results of three randomized splits indicated that robust, simple, predictive, and reliable models were obtained for different sets. From the modelling results, important descriptors were identified to enhance and reduce the larvicidal activity of compounds. Based on the identified important descriptors, some new structures of larvicidal compounds were proposed. The larvicidal activity of novel molecules designed further was supported by docking studies. Using the simple QSAR model, one can predict pLC50 of new similarity larvicidal phytocompounds.


Subject(s)
Aedes/drug effects , Insecticides/pharmacology , Mosquito Vectors/drug effects , Quantitative Structure-Activity Relationship , Aedes/growth & development , Animals , Insecticides/chemistry , Larva/drug effects , Mosquito Vectors/growth & development
15.
PLoS Negl Trop Dis ; 14(9): e0008576, 2020 09.
Article in English | MEDLINE | ID: mdl-32881865

ABSTRACT

BACKGROUND: The ability of cluster-randomized trials to capture mass or indirect effects is one reason for their increasing use to test interventions against vector-borne diseases such as malaria and dengue. For the same reason, however, the independence of clusters may be compromised if the distances between clusters is too small to ensure independence. In other words they may be subject to spillover effects. METHODS: We distinguish two types of spatial spillover effect: between-cluster dependence in outcomes, or spillover dependence; and modification of the intervention effect according to distance to the intervention arm, or spillover indirect effect. We estimate these effects in trial of insecticide-treated materials against the dengue mosquito vector, Aedes aegypti, in Venezuela, the endpoint being the Breteau index. We use a novel random effects Poisson spatial regression model. Spillover dependence is incorporated via an orthogonalized intrinsic conditional autoregression (ICAR) model. Spillover indirect effects are incorporated via the number of locations within a certain radius, set at 200m, that are in the intervention arm. RESULTS: From the model with ICAR spatial dependence, and the degree of surroundedness, the intervention effect is estimated as 0.74-favouring the intervention-with a 95% credible interval of 0.34 to 1.69. The point estimates are stronger with increasing surroundedness within intervention locations. CONCLUSION: In this trial there is some evidence of a spillover indirect effect of the intervention, with the Breteau index tending to be lower in locations which are more surrounded by locations in the intervention arm.


Subject(s)
Aedes/drug effects , Insecticides/pharmacology , Mosquito Control/methods , Mosquito Vectors/drug effects , Aedes/physiology , Animals , Dengue/transmission , Humans , Mosquito Vectors/physiology , Spatial Analysis , Venezuela
16.
PLoS Negl Trop Dis ; 14(8): e0008669, 2020 08.
Article in English | MEDLINE | ID: mdl-32866146

ABSTRACT

Exposure of adult mosquitoes to pyriproxyfen (PPF), an analog of insect juvenile hormone (JH), has shown promise to effectively sterilize female mosquitoes. However, the underlying mechanisms of the PPF-induced decrease in mosquito fecundity are largely unknown. We performed a comprehensive study to dissect the mode of PPF action in Aedes aegypti mosquitoes. Exposure to PPF prompted the overgrowth of primary follicles in sugar-fed Ae. aegypti females but blocked the development of primary follicles at Christopher's Stage III after blood feeding. Secondary follicles were precociously activated in PPF-treated mosquitoes. Moreover, PPF substantially altered the expression of many genes that are essential for mosquito physiology and oocyte development in the fat body and ovary. In particular, many metabolic genes were differentially expressed in response to PPF treatment, thereby affecting the mobilization and utilization of energy reserves. Furthermore, PPF treatment on the previtellogenic female adults considerably modified mosquito responses to JH and 20-hydroxyecdysone (20E), two major hormones that govern mosquito reproduction. Krüppel homolog 1, a JH-inducible transcriptional regulator, showed consistently elevated expression after PPF exposure. Conversely, PPF upregulated the expression of several key players of the 20E regulatory cascades, including HR3 and E75A, in the previtellogenic stage. After blood-feeding, the expression of these 20E response genes was significantly weaker in PPF-treated mosquitoes than the solvent-treated control groups. RNAi-mediated knockdown of the Methoprene-tolerant (Met) protein, the JH receptor, partially rescued the impaired follicular development after PPF exposure and substantially increased the hatching of the eggs produced by PPF-treated female mosquitoes. Thus, the results suggested that PPF relied on Met to exert its sterilizing effects on female mosquitoes. In summary, this study finds that PPF exposure disturbs normal hormonal responses and metabolism in Ae. aegypti, shedding light on the molecular targets and the downstream signaling pathways activated by PPF.


Subject(s)
Aedes/drug effects , Culicidae/drug effects , Insecticides/pharmacology , Methoprene/metabolism , Sterilization , Animals , Ecdysterone/pharmacology , Fat Body/growth & development , Female , Glycogen/metabolism , Insect Proteins/genetics , Juvenile Hormones/pharmacology , Ovary/growth & development , Pyridines , RNA Interference , Triglycerides/metabolism
17.
PLoS One ; 15(8): e0237353, 2020.
Article in English | MEDLINE | ID: mdl-32785255

ABSTRACT

Airborne spatial repellency (SR) is characterized and distinguished from other chemical actions including contact locomotor excitation and toxicity. The use of volatile spatial repellents is a potential new intervention class for combatting mosquito-borne pathogen transmission; therefore, continuing investigations on the actions of these chemicals that modify mosquito host-seeking behavior (i.e., bite prevention) is needed. The objective of this study is to characterize the key behavioral avoidance actions of transfluthrin (TFT) to advance spatial repellent development into practical products. Behavioral avoidance responses were observed for adult laboratory strains of Aedes aegypti, Anopheles minimus and An. dirus, and two field populations of An. harrisoni and Ae. aegypti, respectively. Established TFT sublethal (LC50 and LC75), lethal concentrations (LC99) and discriminating concentrations (DCs) were selected corresponding to each mosquito test species. Spatial repellency and contact excitation ('irritancy') responses on adult mosquitoes to TFT were assessed using an excito-repellency assay system. At LC50, TFT exhibited strong avoidance with An. minimus (60.1% escape) and An. dirus (80% escape) laboratory strains, showing between 12 and 16x greater escape response than Ae. aegypti (5% escape). Repellency responses for field collected Ae. aegypti and An. harrisoni were 54.9 and 47.1% escape, respectively. After adjusting the initial contact escape response (a measure of combined irritancy and repellency) to estimate only escape due to contact, the LC50 and LC99 showed moderate escape irritancy with laboratory Ae. aegypti (41.4% escape) and no contact activity against the field population. Adjustment showed only weak contact activity (16.1% escape) in laboratory An. minimus at LC50. Spatial repellency is the predominant mode of action of TFT among colonized and field mosquitoes used in this study. Established baseline (susceptible) dose-response curves assist in optimizing SR products for mosquito control and pathogen transmission prevention.


Subject(s)
Behavior, Animal/drug effects , Cyclopropanes/pharmacology , Fluorobenzenes/pharmacology , Insect Repellents/pharmacology , Mosquito Vectors/drug effects , Volatile Organic Compounds/pharmacology , Aedes/drug effects , Aedes/physiology , Animals , Anopheles/drug effects , Anopheles/physiology , Avoidance Learning , Dose-Response Relationship, Drug , Female , Mosquito Control/methods , Mosquito Vectors/physiology , Vector Borne Diseases/prevention & control
18.
Ecotoxicol Environ Saf ; 204: 111034, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32758695

ABSTRACT

Trehalose is the major blood sugar in insects; it not only serves as an energy source but also plays important roles in physiological responses to adverse conditions. However, only a few studies have explored the effects of heavy metal exposure stress on trehalose metabolism in insects. Therefore, in this study, we examined the effects of cadmium stress on changes in trehalose metabolism in Aedes albopictus. Three concentrations of cadmium (0.005, 0.01, and 0.1 mg/L) were selected for evaluation of long-term stress in Ae. albopictus (from eggs to adults); Ae. albopictus in double-distilled water was used as the control group. The trehalose and glucose contents, trehalase activity, and trehalose metabolism-related gene expression were determined. The effects of long-term cadmium exposure on growth, development, and reproduction were also assessed. Trehalose contents were increased, whereas glucose contents and trehalase activity were decreased in Ae. albopictus following long-term exposure to low concentrations of cadmium compared with those in untreated individuals. Moreover, the expression of trehalose-6-phosphate synthase was upregulated, and that of trehalase was downregulated, indicating that Ae. albopictus may enhance trehalose synthesis to resist cadmium stress. Cadmium exposure also caused Ae. albopictus individuals to become smaller with a longer developmental duration, whereas both reproduction and hatching rates of the offspring were decreased compared with those in the control group. Our findings demonstrated that cadmium exposure affected the morphology, physiology, and biochemistry of Ae. albopictus. These findings also confirmed the role of trehalose in the response of Ae. albopictus to cadmium stress, providing insights into the effects of heavy metal stress on trehalose metabolism in an insect model.


Subject(s)
Aedes/drug effects , Cadmium/adverse effects , Trehalose/metabolism , Water Pollutants, Chemical/adverse effects , Aedes/growth & development , Aedes/metabolism , Animals , Female , Larva/drug effects , Larva/growth & development , Larva/metabolism , Ovum/drug effects , Ovum/growth & development , Ovum/metabolism , Pupa/drug effects , Pupa/growth & development , Pupa/metabolism
19.
PLoS Negl Trop Dis ; 14(7): e0008490, 2020 07.
Article in English | MEDLINE | ID: mdl-32716942

ABSTRACT

Owing to the increased reports in Aedes-borne diseases in the Caribbean and Latin America, the United States Agency for International Development assisted the Jamaican Ministry of Health and Wellness in conducting insecticide susceptibility tests on Aedes aegypti populations. Sentinel sites were established in seven parishes of Jamaica (St. Catherine, Kingston and St. Andrew, St. Thomas, Portland, St. Mary and St. Ann) and Aedes aegypti eggs were collected, reared to adults per collected population and their susceptibility to varying pyrethroids and organophosphates were tested using the World Health Organization paper bioassays for these insecticides. The Centers for Disease Control and Prevention bottle bioassay was used to assess susceptibility to the carbamate, bendiocarb. The voltage gated sodium channel gene mutations V1016I and I1011V, normally associated with pyrethroid resistance, were also analysed. The results showed that Aedes aegypti collected from all parishes exhibited resistance to pyrethroids at the following concentrations, permethrin 0.25-2.5%; deltamethrin 0.03-0.15%; lambda-cyhalothrin 0.03-0.3%; and etofenprox 0.5-2.5%. The insecticide deltamethrin at concentration 0.3% was the only pyrethroid tested that resulted in high mortality, 94.9 ± 0.34% knockdown within 1 hour of exposure and 98.95 ± 0.01% mortality (p <0.01) at 24 hours post exposure. The frequency of the voltage gated sodium channel gene mutation V1016I was high in the tested population, possibly accounting for the reduced sensitivity to pyrethroids. Organophosphate resistance was also observed in all populations tested. Mortality rates for 0.8% Malathion was 0.8 ± 0.70-60.68 ± 0.38% after 24 hour and 0.00-47.10 ± 3.02%, for pirimiphos-methyl 0.21%. Bendiocarb applied as 12.5 µg/ bottle resulted in mortality rates of 76.25 ± 4.30-100 ± 0.00% after 30 minutes of exposure. The results showed that Ae. aegypti from the seven parishes analysed demonstrated resistance to the insecticides tested. Deltamethrin and bendiocarb at concentrations 0.3% and 12.5µg respectively, were considered most effective, causing high mortality in the local populations. Routine monitoring and evaluations of Ae. aegypti populations from the included parishes are recommended. Additionally, the study results represent the most comprehensive testing to date with local Aedes aegypti populations distributed across different parishes of Jamaica and should be useful to guide national and sub national strategies for vector control and surveillance.


Subject(s)
Aedes/drug effects , Insecticide Resistance , Insecticides/pharmacology , Animals , Female , Jamaica
20.
PLoS One ; 15(7): e0235740, 2020.
Article in English | MEDLINE | ID: mdl-32678859

ABSTRACT

This study evaluated the larvicidal activity of Origanum majorana Linnaeus essential oil, identified the chemical composition, evaluated the antimicrobial, cytotoxic and antioxidant potential. The larvicidal activity was evaluated against larvae of the third stage of Aedes aegypti Linaeus, whereas the chemical composition was identified by gas chromatography coupled to mass spectrometer, the antimicrobial activity was carried out against the bacteria Pseudomonas aeruginosa, Escherichia coli and Staphylococcus auereus, the antioxidant activity was evaluated from of 2.2-diphenyl-1-picryl-hydrazila sequestration and Artemia salina Leach cytotoxicity. Regarding to the results, the larvicidal activity showed that O. majorana L. essential oil caused high mortality in A. aegypti L. larvae. In the chromatographic analysis, the main component found in O. majorana L. essential oil was pulegone (57.05%), followed by the other components verbenone (16.92%), trans-p-menthan-2-one (8.57%), iso-menthone (5.58%), piperitone (2.83%), 3-octanol (2.35%) and isopulegol (1.47%). The antimicrobial activity showed that E. coli and P. aeruginosa bacteria were more sensitive to oil than S. aureus, which was resistant at all concentrations. Essential oil did not present antioxidant activity, but it has high cytotoxic activity against A. salina L.


Subject(s)
Aedes/drug effects , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Insecticides/pharmacology , Larva/drug effects , Oils, Volatile/pharmacology , Origanum/chemistry , Animals , Anti-Bacterial Agents/chemistry , Antioxidants/pharmacology , Bacteria/growth & development , Escherichia coli/drug effects , Escherichia coli/growth & development , Plant Leaves/chemistry , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/growth & development , Staphylococcus aureus/drug effects , Staphylococcus aureus/growth & development
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