<p>Asymmetrical and symmetrical actin clouds (<b>A</b>) as well as tail-like actin clouds (<b>B</b>) are present around GFP-Pb (red and grey: mCherry::β-actin; green: GFP-Pb), surface plots represent the... more
<p>Asymmetrical and symmetrical actin clouds (<b>A</b>) as well as tail-like actin clouds (<b>B</b>) are present around GFP-Pb (red and grey: mCherry::β-actin; green: GFP-Pb), surface plots represent the intensity of the pixels of the mCherry::β-actin channel in the selected region (square). (<b>C</b>) Translocation of a GFP-Pb, associated with a tail-like actin cloud. The tracked path is indicated in blue (red and grey: mCherry::β-actin; green: GFP-Pb). Scale bars represent 10 µm. Some frames present the same time points as the acquisition interval between individual images was 20 s ( = 0.0056 h) and thus too small to annotate in consecutive frames, when using a time scale of hours.</p
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Despite considerable success in controlling malaria worldwide, progress toward achieving malaria elimination has largely stalled. In particular, strategies to overcome roadblocks in malaria control and elimination in Africa are critical... more
Despite considerable success in controlling malaria worldwide, progress toward achieving malaria elimination has largely stalled. In particular, strategies to overcome roadblocks in malaria control and elimination in Africa are critical to achieving worldwide malaria elimination goals—this continent carries 94% of the global malaria case burden. To identify key areas for targeted efforts, we combined a comprehensive review of current literature with direct feedback gathered from frontline malaria workers, leaders, and scholars from Africa. Our analysis identified deficiencies in human resources, training, and capacity building at all levels, from research and development to community involvement. Addressing these needs will require active and coordinated engagement of stakeholders as well as implementation of effective strategies, with malaria-endemic countries owning the relevant processes. This paper reports those valuable identified needs and their concomitant opportunities to ac...
Wolbachiainfections are a fascinating example of reproductive parasitism with strong potential to combat vector-borne diseases, due to their combined ability to spread in insect populations and block pathogen replication. Though... more
Wolbachiainfections are a fascinating example of reproductive parasitism with strong potential to combat vector-borne diseases, due to their combined ability to spread in insect populations and block pathogen replication. Though theWolbachiafactors mediating the notable reproductive manipulation cytoplasmic incompatibility (CI) have now been identified as prophage WO genescifAandcifB, the relative role of these genes is still intensely debated, with different models claiming that CI requires either both factors orcifBalone. Here we investigated whethercifAandcifBare sufficient to induce conditional sterility in the major malaria vectorAnopheles gambiae, a species that appears to have limited susceptibility to invasion byWolbachia. We report that CI can be fully recapitulated in these mosquitoes, and thatcifBis sufficient to cause this reproductive manipulation.cifB-induced sterility is fully rescued by high levels ofcifAexpression in females. Surprisingly, however, whencifAis highly...
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An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely... more
An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Plasmodium sporozoites are transmitted by Anopheles mosquitoes and infect hepatocytes, where a single sporozoite replicates into thousands of merozoites inside a parasitophorous vacuole. The nature of the Plasmodium-host cell interface,... more
Plasmodium sporozoites are transmitted by Anopheles mosquitoes and infect hepatocytes, where a single sporozoite replicates into thousands of merozoites inside a parasitophorous vacuole. The nature of the Plasmodium-host cell interface, as well as the interactions occurring between these two organisms, remains largely unknown. Here we show that highly dynamic hepatocyte actin reorganization events occur around developing Plasmodium berghei parasites inside human hepatoma cells. Actin reorganization is most prominent between 10 to 16 hours post infection and depends on the actin severing and capping protein, gelsolin. Live cell imaging studies also suggest that the hepatocyte cytoskeleton may
Wolbachia, a maternally inherited intracellular bacterial species, can manipulate host insect reproduction by cytoplasmic incompatibility (CI), which results in embryo lethality in crosses between infected males and uninfected females. CI... more
Wolbachia, a maternally inherited intracellular bacterial species, can manipulate host insect reproduction by cytoplasmic incompatibility (CI), which results in embryo lethality in crosses between infected males and uninfected females. CI is encoded by two prophage genes, cifA and cifB. Wolbachia, coupled with the sterile insect technique, has been used in field trials to control populations of the dengue vector Aedes albopictus, but CI-inducing strains are not known to infect the malaria vector Anopheles gambiae. Here we show that cifA and cifB can induce conditional sterility in the malaria vector An. gambiae. We used transgenic expression of these Wolbachia-derived genes in the An. gambiae germline to show that cifB is sufficient to cause embryonic lethality and that cifB-induced sterility is rescued by cifA expression in females. When we co-expressed cifA and cifB in male mosquitoes, the CI phenotype was attenuated. In female mosquitoes, cifB impaired fertility, which was overco...
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Antimalarial drugs have thus far been derived mainly from two sources - natural products and synthetic 'drug-like' compounds. We hypothesized that antimalarial agents with novel mechanisms of action might be discovered using a... more
Antimalarial drugs have thus far been derived mainly from two sources - natural products and synthetic 'drug-like' compounds. We hypothesized that antimalarial agents with novel mechanisms of action might be discovered using a diverse collection of synthetic compounds having three-dimensional features reminiscent of natural products and underrepresented in typical screening collections. We identified such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. The bicylic azetidines display single low-dose cure with activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to cure and prevent transmission of the disease as well as protect populations at risk, all in a single oral exposure, and highlight the strength of diversity-oriented synthesis to reveal promi...
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A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry... more
A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain...
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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 traits underlying male mating success are largely unknown. Here, we... more
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 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 determinants 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 suggest that CHC abundance may be subject to sexual selection in addition to selection by insecticide pressure. This has implications for insecticide resistance management, as these traits m...
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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... more
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 ...