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Transmissibility of clinically relevant atovaquone-resistant Plasmodium falciparum by anopheline mosquitoes

Rising numbers of malaria cases and deaths underscore the need for new interventions. Long-acting injectable medications, such as those now in use for HIV prophylaxis, offer the prospect of a malaria “chemical vaccine”, combining the efficacy of a drug (like atovaquone) with the durability of a biol...

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Autores principales: Balta, Victoria A., Stiffler, Deborah, Sayeed, Abeer, Tripathi, Abhai K., Elahi, Rubayet, Mlambo, Godfree, Bakshi, Rahul P., Dziedzic, Amanda G., Jedlicka, Anne E., Nenortas, Elizabeth, Romero-Rodriguez, Keyla, Canonizado, Matthew A., Mann, Alexis, Owen, Andrew, Sullivan, David J., Prigge, Sean T., Sinnis, Photini, Shapiro, Theresa A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9934642/
https://www.ncbi.nlm.nih.gov/pubmed/36798298
http://dx.doi.org/10.1101/2023.02.07.527535
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author Balta, Victoria A.
Stiffler, Deborah
Sayeed, Abeer
Tripathi, Abhai K.
Elahi, Rubayet
Mlambo, Godfree
Bakshi, Rahul P.
Dziedzic, Amanda G.
Jedlicka, Anne E.
Nenortas, Elizabeth
Romero-Rodriguez, Keyla
Canonizado, Matthew A.
Mann, Alexis
Owen, Andrew
Sullivan, David J.
Prigge, Sean T.
Sinnis, Photini
Shapiro, Theresa A.
author_facet Balta, Victoria A.
Stiffler, Deborah
Sayeed, Abeer
Tripathi, Abhai K.
Elahi, Rubayet
Mlambo, Godfree
Bakshi, Rahul P.
Dziedzic, Amanda G.
Jedlicka, Anne E.
Nenortas, Elizabeth
Romero-Rodriguez, Keyla
Canonizado, Matthew A.
Mann, Alexis
Owen, Andrew
Sullivan, David J.
Prigge, Sean T.
Sinnis, Photini
Shapiro, Theresa A.
author_sort Balta, Victoria A.
collection PubMed
description Rising numbers of malaria cases and deaths underscore the need for new interventions. Long-acting injectable medications, such as those now in use for HIV prophylaxis, offer the prospect of a malaria “chemical vaccine”, combining the efficacy of a drug (like atovaquone) with the durability of a biological vaccine. Of concern, however, is the possible selection and transmission of drug-resistant parasites. We addressed this question by generating clinically relevant, highly atovaquone-resistant, Plasmodium falciparum mutants competent to infect mosquitoes. Isogenic paired strains, that differ only by a single Y268S mutation in cytochrome b, were evaluated in parallel in southeast Asian (Anopheles stephensi) or African (Anopheles gambiae) mosquitoes, and thence in humanized mice. Fitness costs of the mutation were evident along the lifecycle, in asexual parasite growth in vitro and in a progressive loss of parasites in the mosquito. In numerous independent experiments, microscopic exam of salivary glands from hundreds of mosquitoes failed to detect even one Y268S sporozoite, a defect not rescued by coinfection with wild type parasites. Furthermore, despite uniformly successful transmission of wild type parasites from An. stephensi to FRG NOD huHep mice bearing human hepatocytes and erythrocytes, multiple attempts with Y268S-fed mosquitoes failed: there was no evidence of parasites in mouse tissues by microscopy, in vitro culture, or PCR. These studies confirm a severe-to-lethal fitness cost of clinically relevant atovaquone-resistant P. falciparum in the mosquito, and they significantly lessen the likelihood of their transmission in the field.
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spelling pubmed-99346422023-02-17 Transmissibility of clinically relevant atovaquone-resistant Plasmodium falciparum by anopheline mosquitoes Balta, Victoria A. Stiffler, Deborah Sayeed, Abeer Tripathi, Abhai K. Elahi, Rubayet Mlambo, Godfree Bakshi, Rahul P. Dziedzic, Amanda G. Jedlicka, Anne E. Nenortas, Elizabeth Romero-Rodriguez, Keyla Canonizado, Matthew A. Mann, Alexis Owen, Andrew Sullivan, David J. Prigge, Sean T. Sinnis, Photini Shapiro, Theresa A. bioRxiv Article Rising numbers of malaria cases and deaths underscore the need for new interventions. Long-acting injectable medications, such as those now in use for HIV prophylaxis, offer the prospect of a malaria “chemical vaccine”, combining the efficacy of a drug (like atovaquone) with the durability of a biological vaccine. Of concern, however, is the possible selection and transmission of drug-resistant parasites. We addressed this question by generating clinically relevant, highly atovaquone-resistant, Plasmodium falciparum mutants competent to infect mosquitoes. Isogenic paired strains, that differ only by a single Y268S mutation in cytochrome b, were evaluated in parallel in southeast Asian (Anopheles stephensi) or African (Anopheles gambiae) mosquitoes, and thence in humanized mice. Fitness costs of the mutation were evident along the lifecycle, in asexual parasite growth in vitro and in a progressive loss of parasites in the mosquito. In numerous independent experiments, microscopic exam of salivary glands from hundreds of mosquitoes failed to detect even one Y268S sporozoite, a defect not rescued by coinfection with wild type parasites. Furthermore, despite uniformly successful transmission of wild type parasites from An. stephensi to FRG NOD huHep mice bearing human hepatocytes and erythrocytes, multiple attempts with Y268S-fed mosquitoes failed: there was no evidence of parasites in mouse tissues by microscopy, in vitro culture, or PCR. These studies confirm a severe-to-lethal fitness cost of clinically relevant atovaquone-resistant P. falciparum in the mosquito, and they significantly lessen the likelihood of their transmission in the field. Cold Spring Harbor Laboratory 2023-02-09 /pmc/articles/PMC9934642/ /pubmed/36798298 http://dx.doi.org/10.1101/2023.02.07.527535 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Balta, Victoria A.
Stiffler, Deborah
Sayeed, Abeer
Tripathi, Abhai K.
Elahi, Rubayet
Mlambo, Godfree
Bakshi, Rahul P.
Dziedzic, Amanda G.
Jedlicka, Anne E.
Nenortas, Elizabeth
Romero-Rodriguez, Keyla
Canonizado, Matthew A.
Mann, Alexis
Owen, Andrew
Sullivan, David J.
Prigge, Sean T.
Sinnis, Photini
Shapiro, Theresa A.
Transmissibility of clinically relevant atovaquone-resistant Plasmodium falciparum by anopheline mosquitoes
title Transmissibility of clinically relevant atovaquone-resistant Plasmodium falciparum by anopheline mosquitoes
title_full Transmissibility of clinically relevant atovaquone-resistant Plasmodium falciparum by anopheline mosquitoes
title_fullStr Transmissibility of clinically relevant atovaquone-resistant Plasmodium falciparum by anopheline mosquitoes
title_full_unstemmed Transmissibility of clinically relevant atovaquone-resistant Plasmodium falciparum by anopheline mosquitoes
title_short Transmissibility of clinically relevant atovaquone-resistant Plasmodium falciparum by anopheline mosquitoes
title_sort transmissibility of clinically relevant atovaquone-resistant plasmodium falciparum by anopheline mosquitoes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9934642/
https://www.ncbi.nlm.nih.gov/pubmed/36798298
http://dx.doi.org/10.1101/2023.02.07.527535
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