Bioluminescence Method for
            <i>In Vitro</i>
            Screening of Plasmodium Transmission-Blocking Compounds

Azevedo, Ricardo Cabral de; Marković, Marija; Machado, Marta; Franke-Fayard, Blandine; Mendes, António M.; Prudêncio, Miguel

doi:10.1128/aac.02699-16

Cited by 27 publications

(25 citation statements)

References 50 publications

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“…A necessary breakthrough towards this end would be the reliable cultivation of oocysts in vitro. Such cultivation has been described before (Al-Olayan et al, 2002) but could not be reproduced robustly in other laboratories (Azevedo et al, 2017).…”

Section: Of 22mentioning

confidence: 99%

Microtubule number and length determine cellular shape and function in Plasmodium

et al. 2019

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Microtubules are cytoskeletal filaments essential for many cellular processes, including establishment and maintenance of polarity, intracellular transport, division and migration. In most metazoan cells, the number and length of microtubules are highly variable, while they can be precisely defined in some protozoan organisms. However, in either case the significance of these two key parameters for cells is not known. Here, we quantitatively studied the impact of modulating microtubule number and length in Plasmodium , the protozoan parasite causing malaria. Using a gene deletion and replacement strategy targeting one out of two α‐tubulin genes, we show that chromosome segregation proceeds in the oocysts even in the absence of microtubules. However, fewer and shorter microtubules severely impaired the formation, motility and infectivity of Plasmodium sporozoites, the forms transmitted by the mosquito, which usually contain 16 microtubules. We found that α‐tubulin expression levels directly determined the number of microtubules, suggesting a high nucleation barrier as supported by a mathematical model. Infectious sporozoites were only formed in parasite lines featuring at least 10 microtubules, while parasites with 9 or fewer microtubules failed to transmit.

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Section: Of 22mentioning

confidence: 99%

Microtubule number and length determine cellular shape and function in Plasmodium

et al. 2019

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“…Systems accessing gametocytogenesis or gametocyte clearance (7)(8)(9)(10)(11)(12)(13)(14) and gametocyte viability (15,16) in high throughput (HT) or semi-HT are available. However, to date only two models, developed using Plasmodium berghei, are able to assess gametocyte function, i.e., gametogenesis, zygote formation, and ookinete morphogenesis, in semi-HT (17) or HT (18).…”

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confidence: 99%

Screening the Pathogen Box for Molecules Active against Plasmodium Sexual Stages Using a New Nanoluciferase-Based Transgenic Line of P. berghei Identifies Transmission-Blocking Compounds

Calit

Dobrescu

Gaitan

et al. 2018

Antimicrob Agents Chemother

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Malaria remains an important parasitic disease with a large morbidity and mortality burden. transmission-blocking (TB) compounds are essential for achieving malaria elimination efforts. Recent efforts to develop high-throughput screening (HTS) methods to identify compounds that inhibit or kill gametocytes, the sexual stage infectious to mosquitoes, have yielded insight into new TB compounds. However, the activities of these compounds against gametes, formed in the first minutes of mosquito infection, are typically not assessed, unless screened in a standard membrane feeding assay, a labor-intensive assay. We demonstrate here the generation of a model for drug screens against gametes and fertilization. The new line, named , was genetically and pharmacologically validated and scalable for HTS. Screening the Pathogen Box from the Medicines for Malaria Venture using the new model identified promising TB compounds. The use of in different libraries of compounds may aid in the identification of transmission-blocking drugs not assessed in screens against asexual stages or gametocytes.

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“…Mitochondria are essential for mosquito stages of the Plasmodium life cycle, as mutations in mitochondrial genes arrest growth and sporulation of oocysts 27–30 . Moreover, inhibition of mitochondrial potential by the antimalarial drug atovaquone inhibits Plasmodium sporogonic development and reduces the number and size of developing EEFs in vitro 31–33 . Together with these findings, our results identify mitochondria as crucial regulators of within-vector Plasmodium proliferation, transmission and within-host virulence.…”

Section: Discussionmentioning

confidence: 99%

Non-competitive resource exploitation within-mosquito shapes evolution of malaria virulence

Costa

Gildenhard

Eldering

et al. 2017

Preprint

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2Malaria is a fatal human parasitic disease transmitted by a mosquito vector. The 3 evolution of within-host malaria virulence has been the focus of many empirical and 4 theoretical studies. However, the vector's contribution to virulence evolution is not well 5 understood. Here we explored how within-vector resource exploitation impacts 6 evolutionary trajectories of within-host Plasmodium virulence. We developed a nested 7 model of within-vector dynamics and malaria epidemiology, which predicted that non-8 competitive resource exploitation within-vector restricts within-host parasite virulence. To 9 validate our model, we experimentally manipulated mosquito lipid trafficking and gauged 10 within-vector parasite development, within-host infectivity and virulence. We found that 11 mosquito-derived lipids determine within-host parasite virulence by shaping development 12 and metabolic activity of transmissible sporozoites. Our findings uncover the role of 13 within-vector environment in regulating within-host Plasmodium virulence and identify

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Bioluminescence Method for In Vitro Screening of Plasmodium Transmission-Blocking Compounds

Cited by 27 publications

References 50 publications

Microtubule number and length determine cellular shape and function in Plasmodium

Microtubule number and length determine cellular shape and function in Plasmodium

Screening the Pathogen Box for Molecules Active against Plasmodium Sexual Stages Using a New Nanoluciferase-Based Transgenic Line of P. berghei Identifies Transmission-Blocking Compounds

Non-competitive resource exploitation within-mosquito shapes evolution of malaria virulence

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