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The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite

The emergence and spread of Plasmodium falciparum parasites resistant to front-line antimalarial artemisinin-combination therapies (ACT) threatens to erase the considerable gains against the disease of the last decade. Here, we develop a large-scale phenotypic screening pipeline and use it to carry...

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Autores principales: Zhang, Min, Wang, Chengqi, Oberstaller, Jenna, Thomas, Phaedra, Otto, Thomas D., Casandra, Debora, Boyapalle, Sandhya, Adapa, Swamy R., Xu, Shulin, Button-Simons, Katrina, Mayho, Matthew, Rayner, Julian C., Ferdig, Michael T., Jiang, Rays H. Y., Adams, John H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316339/
https://www.ncbi.nlm.nih.gov/pubmed/34315897
http://dx.doi.org/10.1038/s41467-021-24814-1
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author Zhang, Min
Wang, Chengqi
Oberstaller, Jenna
Thomas, Phaedra
Otto, Thomas D.
Casandra, Debora
Boyapalle, Sandhya
Adapa, Swamy R.
Xu, Shulin
Button-Simons, Katrina
Mayho, Matthew
Rayner, Julian C.
Ferdig, Michael T.
Jiang, Rays H. Y.
Adams, John H.
author_facet Zhang, Min
Wang, Chengqi
Oberstaller, Jenna
Thomas, Phaedra
Otto, Thomas D.
Casandra, Debora
Boyapalle, Sandhya
Adapa, Swamy R.
Xu, Shulin
Button-Simons, Katrina
Mayho, Matthew
Rayner, Julian C.
Ferdig, Michael T.
Jiang, Rays H. Y.
Adams, John H.
author_sort Zhang, Min
collection PubMed
description The emergence and spread of Plasmodium falciparum parasites resistant to front-line antimalarial artemisinin-combination therapies (ACT) threatens to erase the considerable gains against the disease of the last decade. Here, we develop a large-scale phenotypic screening pipeline and use it to carry out a large-scale forward-genetic phenotype screen in P. falciparum to identify genes allowing parasites to survive febrile temperatures. Screening identifies more than 200 P. falciparum mutants with differential responses to increased temperature. These mutants are more likely to be sensitive to artemisinin derivatives as well as to heightened oxidative stress. Major processes critical for P. falciparum tolerance to febrile temperatures and artemisinin include highly essential, conserved pathways associated with protein-folding, heat shock and proteasome-mediated degradation, and unexpectedly, isoprenoid biosynthesis, which originated from the ancestral genome of the parasite’s algal endosymbiont-derived plastid, the apicoplast. Apicoplast-targeted genes in general are upregulated in response to heat shock, as are other Plasmodium genes with orthologs in plant and algal genomes. Plasmodium falciparum parasites appear to exploit their innate febrile-response mechanisms to mediate resistance to artemisinin. Both responses depend on endosymbiont-derived genes in the parasite’s genome, suggesting a link to the evolutionary origins of Plasmodium parasites in free-living ancestors.
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spelling pubmed-83163392021-08-03 The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite Zhang, Min Wang, Chengqi Oberstaller, Jenna Thomas, Phaedra Otto, Thomas D. Casandra, Debora Boyapalle, Sandhya Adapa, Swamy R. Xu, Shulin Button-Simons, Katrina Mayho, Matthew Rayner, Julian C. Ferdig, Michael T. Jiang, Rays H. Y. Adams, John H. Nat Commun Article The emergence and spread of Plasmodium falciparum parasites resistant to front-line antimalarial artemisinin-combination therapies (ACT) threatens to erase the considerable gains against the disease of the last decade. Here, we develop a large-scale phenotypic screening pipeline and use it to carry out a large-scale forward-genetic phenotype screen in P. falciparum to identify genes allowing parasites to survive febrile temperatures. Screening identifies more than 200 P. falciparum mutants with differential responses to increased temperature. These mutants are more likely to be sensitive to artemisinin derivatives as well as to heightened oxidative stress. Major processes critical for P. falciparum tolerance to febrile temperatures and artemisinin include highly essential, conserved pathways associated with protein-folding, heat shock and proteasome-mediated degradation, and unexpectedly, isoprenoid biosynthesis, which originated from the ancestral genome of the parasite’s algal endosymbiont-derived plastid, the apicoplast. Apicoplast-targeted genes in general are upregulated in response to heat shock, as are other Plasmodium genes with orthologs in plant and algal genomes. Plasmodium falciparum parasites appear to exploit their innate febrile-response mechanisms to mediate resistance to artemisinin. Both responses depend on endosymbiont-derived genes in the parasite’s genome, suggesting a link to the evolutionary origins of Plasmodium parasites in free-living ancestors. Nature Publishing Group UK 2021-07-27 /pmc/articles/PMC8316339/ /pubmed/34315897 http://dx.doi.org/10.1038/s41467-021-24814-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhang, Min
Wang, Chengqi
Oberstaller, Jenna
Thomas, Phaedra
Otto, Thomas D.
Casandra, Debora
Boyapalle, Sandhya
Adapa, Swamy R.
Xu, Shulin
Button-Simons, Katrina
Mayho, Matthew
Rayner, Julian C.
Ferdig, Michael T.
Jiang, Rays H. Y.
Adams, John H.
The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite
title The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite
title_full The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite
title_fullStr The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite
title_full_unstemmed The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite
title_short The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite
title_sort apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316339/
https://www.ncbi.nlm.nih.gov/pubmed/34315897
http://dx.doi.org/10.1038/s41467-021-24814-1
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