Cargando…

A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites

Malaria parasites rely on a plastid organelle for survival during the blood stages of infection. However, the entire organelle is dispensable as long as the isoprenoid precursor, isopentenyl pyrophosphate (IPP), is supplemented in the culture medium. We engineered parasites to produce isoprenoid pre...

Descripción completa

Detalles Bibliográficos
Autores principales: Swift, Russell P., Rajaram, Krithika, Liu, Hans B., Dziedzic, Amanda, Jedlicka, Anne E., Roberts, Aleah D., Matthews, Krista A., Jhun, Hugo, Bumpus, Namandje N., Tewari, Shivendra G., Wallqvist, Anders, Prigge, Sean T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046295/
https://www.ncbi.nlm.nih.gov/pubmed/32059044
http://dx.doi.org/10.1371/journal.ppat.1008316
_version_ 1783501941207203840
author Swift, Russell P.
Rajaram, Krithika
Liu, Hans B.
Dziedzic, Amanda
Jedlicka, Anne E.
Roberts, Aleah D.
Matthews, Krista A.
Jhun, Hugo
Bumpus, Namandje N.
Tewari, Shivendra G.
Wallqvist, Anders
Prigge, Sean T.
author_facet Swift, Russell P.
Rajaram, Krithika
Liu, Hans B.
Dziedzic, Amanda
Jedlicka, Anne E.
Roberts, Aleah D.
Matthews, Krista A.
Jhun, Hugo
Bumpus, Namandje N.
Tewari, Shivendra G.
Wallqvist, Anders
Prigge, Sean T.
author_sort Swift, Russell P.
collection PubMed
description Malaria parasites rely on a plastid organelle for survival during the blood stages of infection. However, the entire organelle is dispensable as long as the isoprenoid precursor, isopentenyl pyrophosphate (IPP), is supplemented in the culture medium. We engineered parasites to produce isoprenoid precursors from a mevalonate-dependent pathway, creating a parasite line that replicates normally after the loss of the apicoplast organelle. We show that carbon-labeled mevalonate is specifically incorporated into isoprenoid products, opening new avenues for researching this essential class of metabolites in malaria parasites. We also show that essential apicoplast proteins, such as the enzyme target of the drug fosmidomycin, can be deleted in this mevalonate bypass parasite line, providing a new method to determine the roles of other important apicoplast-resident proteins. Several antibacterial drugs kill malaria parasites by targeting basic processes, such as transcription, in the organelle. We used metabolomic and transcriptomic methods to characterize parasite metabolism after azithromycin treatment triggered loss of the apicoplast and found that parasite metabolism and the production of apicoplast proteins is largely unaltered. These results provide insight into the effects of apicoplast-disrupting drugs, several of which have been used to treat malaria infections in humans. Overall, the mevalonate bypass system provides a way to probe essential aspects of apicoplast biology and study the effects of drugs that target apicoplast processes.
format Online
Article
Text
id pubmed-7046295
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-70462952020-03-09 A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites Swift, Russell P. Rajaram, Krithika Liu, Hans B. Dziedzic, Amanda Jedlicka, Anne E. Roberts, Aleah D. Matthews, Krista A. Jhun, Hugo Bumpus, Namandje N. Tewari, Shivendra G. Wallqvist, Anders Prigge, Sean T. PLoS Pathog Research Article Malaria parasites rely on a plastid organelle for survival during the blood stages of infection. However, the entire organelle is dispensable as long as the isoprenoid precursor, isopentenyl pyrophosphate (IPP), is supplemented in the culture medium. We engineered parasites to produce isoprenoid precursors from a mevalonate-dependent pathway, creating a parasite line that replicates normally after the loss of the apicoplast organelle. We show that carbon-labeled mevalonate is specifically incorporated into isoprenoid products, opening new avenues for researching this essential class of metabolites in malaria parasites. We also show that essential apicoplast proteins, such as the enzyme target of the drug fosmidomycin, can be deleted in this mevalonate bypass parasite line, providing a new method to determine the roles of other important apicoplast-resident proteins. Several antibacterial drugs kill malaria parasites by targeting basic processes, such as transcription, in the organelle. We used metabolomic and transcriptomic methods to characterize parasite metabolism after azithromycin treatment triggered loss of the apicoplast and found that parasite metabolism and the production of apicoplast proteins is largely unaltered. These results provide insight into the effects of apicoplast-disrupting drugs, several of which have been used to treat malaria infections in humans. Overall, the mevalonate bypass system provides a way to probe essential aspects of apicoplast biology and study the effects of drugs that target apicoplast processes. Public Library of Science 2020-02-14 /pmc/articles/PMC7046295/ /pubmed/32059044 http://dx.doi.org/10.1371/journal.ppat.1008316 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Swift, Russell P.
Rajaram, Krithika
Liu, Hans B.
Dziedzic, Amanda
Jedlicka, Anne E.
Roberts, Aleah D.
Matthews, Krista A.
Jhun, Hugo
Bumpus, Namandje N.
Tewari, Shivendra G.
Wallqvist, Anders
Prigge, Sean T.
A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites
title A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites
title_full A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites
title_fullStr A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites
title_full_unstemmed A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites
title_short A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites
title_sort mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046295/
https://www.ncbi.nlm.nih.gov/pubmed/32059044
http://dx.doi.org/10.1371/journal.ppat.1008316
work_keys_str_mv AT swiftrussellp amevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT rajaramkrithika amevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT liuhansb amevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT dziedzicamanda amevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT jedlickaannee amevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT robertsaleahd amevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT matthewskristaa amevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT jhunhugo amevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT bumpusnamandjen amevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT tewarishivendrag amevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT wallqvistanders amevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT priggeseant amevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT swiftrussellp mevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT rajaramkrithika mevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT liuhansb mevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT dziedzicamanda mevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT jedlickaannee mevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT robertsaleahd mevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT matthewskristaa mevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT jhunhugo mevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT bumpusnamandjen mevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT tewarishivendrag mevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT wallqvistanders mevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites
AT priggeseant mevalonatebypasssystemfacilitateselucidationofplastidbiologyinmalariaparasites