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The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite
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The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite
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Journal Article
The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite
2021
Overview
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.
Repeating fever is a hallmark of malaria. Here, a large-scale forward genetic screen in malaria-causing Plasmodium falciparum identifies genes associated with parasite tolerance to host fever, including apicoplast targeted isoprenoid biosynthesis—sharing features with artemisinin resistance.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 38/39
/ 38/91
/ 45/23
/ 45/77
/ Algae
/ Animals
/ Drug Resistance - drug effects
/ Fever
/ Gene Expression Regulation - drug effects
/ Genes
/ Genomes
/ Heat-Shock Response - drug effects
/ Humanities and Social Sciences
/ Malaria
/ Malaria, Falciparum - parasitology
/ Mutants
/ Plasmodium falciparum - genetics
/ Science
/ Signal Transduction - drug effects
/ Transcription, Genetic - drug effects
