Biology subjects

Paton, D. G.

Publications and source records attributed to Paton, D. G..

6 recordsLinked to original sources

bioRxiv2025

Anti-malarial contact dependent blocking of transmission of Plasmodium vivax by Anopheles darlingi mosquito vector

Malaria, caused by protozoa of the genus Plasmodium and transmitted to humans through the bite of mosquitoes of the genus Anopheles, remains a public health problem. Long-Lasting Insecticide -treated bed Nets (LLINS) and Indoor Residual Spraying (IRS) represent the main vector control measures for malaria prevention. However, to address the concerns of mosquito resistance to pyrethroids, other malaria control strategies are being explored for effectively blocking malaria transmission by eliminating or reducing the parasite in the vector. This study evaluated the use of antimalarials through tarsal contact of female Anopheles darlingi infected with Plasmodium vivax via a Direct Membrane Feeding Assay (DMFA). Female An. darlingi were exposed tarsally using Petri dishes impregnated with antimalarials at 1 mmol/m2 for exposure times of 6 or 60 minutes. Among the antimalarials evaluated were Atovaquone (ATQ), Tafenoquine (TQ), Chloroquine (CQ), Mefloquine (MQ), Primaquine (PQ), and the compound Nanchangmycin (NCG). Atovaquone was the only antimalarial evaluated before and after DMFA at exposure times of 60 min and 6 min. The results demonstrate complete elimination of P. vivax in female An. darlingi exposed to ATQ by tarsal contact 60 min before infection. ATQ was also effective 6 min before or after infection, reducing infection prevalence. In addition, MQ also significantly reduced infection intensity, but there was no difference in infection prevalence. No significant differences were observed for the other antimalarials. Author SummaryMalaria caused by Plasmodium vivax is the most prevalent in the Amazon region, with Anopheles darlingi as its main vector. Mosquito resistance to pyrethroid insecticides, already described in African countries, also raises an alarm for areas endemic for vivax malaria. Given this scenario, strategies that involve blocking parasite transmission have proven effective. Our study involved the transmission-blocking potential of antimalarials administered via tarsal contact to An. darlingi infected with P. vivax. Tarsal exposure involves the direct contact of the mosquitoes tarsi with surfaces impregnated with antimalarials. We speculate that in a real-world setting, this approach could be translated by treating surfaces like bed nets, eaves, or resting sites with the compounds, exploiting the natural resting and host-seeking behaviors of mosquitoes that bring their tarsi into contact with these treated substrates. If the drugs/compounds penetrate the cuticle, they could impact the parasites biological cycle within the vector. Our results confirmed this potential, Atovaquone was able to eliminate or reduce P. vivax from the midguts of An. darlingi at different exposure times, demonstrating successful uptake through the tarsi. Mefloquine was also reduced parasite intensity via tarsal contact. These findings reinforce the potential of this approach as a complementary tool in malaria control.

zoology↗

bioRxiv2023

CRISPR-mediated germline mutagenesis for genetic sterilization of Anopheles gambiae males.

Rapid spread of insecticide resistance among anopheline mosquitoes threatens malaria elimination efforts, necessitating development of alternative vector control technologies. Sterile Insect Technique (SIT) has been successfully implemented in multiple insect pests to suppress field populations by the release of large numbers of sterile males, yet it has proven difficult to adapt to Anopheles vectors. Here we outline adaptation of a CRISPR-based genetic sterilization system to selectively ablate male sperm cells in the malaria mosquito Anopheles gambiae. We achieve robust mosaic biallelic mutagenesis of zero population growth (zpg, a gene essential for differentiation of germ cells) in F1 individuals after intercrossing a germline-expressing Cas9 transgenic line to a line expressing zpg-targeting gRNAs. Approximately 95% of mutagenized males display complete genetic sterilization, and cause similarly high levels of infertility in their female mates. Using a fluorescence reporter that allows detection of the germline leads to a 100% accurate selection of spermless males, improving the system. These males cause a striking reduction in mosquito population size when released at field-like frequencies in competition cages against wild type males. These findings demonstrate that such a genetic system could be adopted for SIT against important malaria vectors.

synthetic biology↗

bioRxiv2021

Cuticular hydrocarbons are associated with mating success and insecticide resistance in malaria vectors

Anopheles coluzzii females, important malaria vectors in Africa, mate only once in their lifetime. Mating occurs in aerial swarms with a high male-to-female ratio, where the traits underlying male mating success are largely unknown. Here, we investigated whether cuticular hydrocarbons (CHCs) influence mating success in natural mating swarms in Burkina Faso. As insecticides are widely used in this area for malaria control, we also determined whether CHCs affect insecticide resistance levels. We find that mated males have higher CHC abundance than unmated controls, suggesting CHCs could be a determinant of mating success. Additionally, mated males have higher insecticide resistance under pyrethroid challenge, and we show a link between resistance intensity and CHC abundance. Taken together, our results reveal overlapping roles played by CHCs in mate choice and insecticide resistance, and point to sexual selection for insecticide resistance traits that limit the efficacy of our best malaria control tools.

ecology↗

bioRxiv2021

Antimalarials in mosquitoes overcome Anopheles and Plasmodium resistance to malaria control strategies

The spread of insecticide resistance in Anopheles mosquitoes and drug resistance in Plasmodium parasites is contributing to a global resurgence of malaria, making the generation of control tools that can overcome these issues an urgent public health priority. We recently showed that the transmission of Plasmodium falciparum parasites can be efficiently blocked when exposing Anopheles gambiae females to antimalarials deposited on a treated surface, with no negative consequences on mosquito fitness. Here, we demonstrate this approach can overcome the hurdles of insecticide resistance in mosquitoes and drug resistant in parasites. We show that the transmission-blocking efficacy of mosquito-targeted antimalarials is maintained when field-derived, insecticide resistant Anopheles are exposed to the potent cytochrome b inhibitor atovaquone, demonstrating that this drug escapes insecticide resistance mechanisms that could potentially interfere with its function. Moreover, this approach prevents transmission of field-derived, artemisinin resistant P. falciparum parasites (Kelch13 C580Y mutant), proving that this strategy could be used to prevent the spread of parasite mutations that induce resistance to front-line antimalarials. Atovaquone is also highly effective at limiting parasite development when ingested by mosquitoes in sugar solutions, including in ongoing infections. These data support the use of mosquito-targeted antimalarials as a promising tool to complement and extend the efficacy of current malaria control interventions. Significance StatementEffective control of malaria is hampered by resistance to vector-targeted insecticides and parasite-targeted drugs. This situation is exacerbated by a critical lack of chemical diversity in both interventions and, as such, new interventions are badly needed. Recent laboratory studies have shown that an alternative approach based on treating Anopheles mosquitoes directly with antimalarial compounds can render the vector incapable of transmitting the Plasmodium parasites that cause malaria. While promising, showing that mosquito-targeted antimalarials remain effective against wild parasites and mosquitoes, including drug- and insecticide-resistant populations, respectively, is crucial to the future viability of this approach. In this study, carried out in the US and Burkina Faso, we show that antimalarial exposure is highly effective, even against extremely resistant mosquitoes, and can block transmission of drug-resistant parasites. By combining lab, and field-based studies in this way we have demonstrated that this novel approach can be effective in areas where conventional control measures are no longer as effective.

microbiology↗

bioRxiv2020

Current estimates of malaria basic reproduction number underestimate parasite transmission efficiency due to multiple blood feeding

Many mosquito species, including the major malaria vector Anopheles gambiae, naturally undergo multiple reproductive cycles of blood feeding, egg development and egg laying in their lifespan. Such complex mosquito behavior is regularly overlooked when mosquitoes are experimentally infected with malaria parasites, limiting our ability to accurately describe potential effects on transmission. Here, we examine how Plasmodium falciparum development and transmission potential is impacted when infected mosquitoes feed an additional time. We measured P. falciparum oocyst size and performed sporozoite time course analyses to determine the parasite’s extrinsic incubation period (EIP), i.e. the time required by parasites to reach infectious sporozoite stages, in An. gambiae females blood fed either once or twice. An additional blood feed at 3 days post infection drastically accelerates oocyst growth rates, causing earlier sporozoite accumulation in the salivary glands, thereby shortening the EIP (reduction of 2.25 ± 0.39 days). Moreover, parasite growth is further accelerated in transgenic mosquitoes with reduced reproductive capacity, which mimic genetic modifications currently proposed in population suppression gene drives. We incorporate our shortened EIP values into a measure of transmission potential, the basic reproduction number R0, and find the average R0 is remarkably higher (range: 10.1%–12.1% increase) across sub-Saharan Africa than when using traditional EIP measurements. These data suggest that malaria elimination may be substantially more challenging and that younger mosquitoes or those with reduced reproductive ability may provide a larger contribution to infection than currently believed. Our findings have profound implications for current and future mosquito control interventions.Significance Statement In natural settings the female Anopheles gambiae mosquito, the major malaria vector, blood feeds multiple times in her lifespan. Here we demonstrate that an additional blood feed accelerates the growth of Plasmodium falciparum malaria parasites in this mosquito. Incorporating these data into a mathematical model across sub-Saharan Africa reveals that malaria transmission potential is likely to be substantially higher than previously thought, making disease elimination more difficult. Additionally, we show that control strategies that manipulate mosquito reproduction with the aim of suppressing Anopheles populations may inadvertently favor malaria transmission. Our data also suggest that parasites can be transmitted by younger mosquitoes, which are less susceptible to insecticide killing, with negative implications for the success of insecticide-based strategies.Competing Interest StatementThe authors have declared no competing interest.View Full Text

microbiology↗

bioRxiv2020

Steroid hormone agonists reduce female fitness in insecticide-resistant Anopheles populations

Insecticide based vector control tools such as insecticide treated bednets and indoor residual spraying represent the cornerstones of malaria control programs. Resistance to chemistries used in these programs is now widespread and represents a significant threat to the gains seen in reducing malaria-related morbidity and mortality. Recently, disruption of the 20-hydroxyecdysone steroid hormone pathway was shown to reduce Plasmodium development time and significantly reduce both longevity and egg production in a laboratory susceptible Anopheles gambiae population. Here, we demonstrate that disruption of this pathway by application of methoxyfenozide (MET) to insecticide resistant An. coluzzii, An. gambiae sl and An. funestus populations significantly reduces egg production in both topical and tarsal application. Moreover, MET reduces adult longevity when applied topically, and tarsally after blood feeding. As the cytochrome p450s elevated in pyrethroid resistant Anopheles only bind MET very weakly, this compound is unlikely to be subject to cross-resistance in a field-based setting. Manipulation of this hormonal signalling pathway therefore represents a potential complementary approach to current malaria control strategies, particularly in areas where high levels of insecticide resistance are compromising existing tools.

pharmacology and toxicology↗