The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite
ABSTRACT Background The emergence and spread ofPlasmodium falciparumparasites resistant to front-line antimalarial artemisinin-combination therapies (ACT) threatens to erase the considerable gains against the disease of the last decade. We developed a new large-scale phenotypic screening pipeline and used it to carry out the first large-scale forward-genetic phenotype screen inP. falciparumto identify genes that allow parasites to survive febrile temperatures.Results Screening identified more than 200P. falciparummutants with differential responses to increased temperature. These mutants were more likely to be sensitive to artemisinin derivatives as well as to heightened oxidative stress. Major processes critical forP. falciparumtolerance to febrile temperatures and artemisinin included 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 were up-regulated in response to heat shock, as were otherPlasmodiumgenes with orthologs in plant and algal genomes.Conclusions Plasmodium falciparumparasites appear to exploit their innate febrile-response mechanisms to mediate resistance to artemisinin. Both responses depend on endosymbiotic cynobacterium-related ancestral genes in the parasite’s genome, suggesting a link to the evolutionary origins ofPlasmodiumparasites in free-living ancestors..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
bioRxiv.org - (2022) vom: 04. Dez. Zur Gesamtaufnahme - year:2022 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zhang, Min [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| doi: |
10.1101/2020.12.10.419788 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI019523793 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI019523793 | ||
| 003 | DE-627 | ||
| 005 | 20230429092246.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 201211s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2020.12.10.419788 |2 doi | |
| 035 | |a (DE-627)XBI019523793 | ||
| 035 | |a (biorXiv)10.1101/2020.12.10.419788 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zhang, Min |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a ABSTRACT Background The emergence and spread ofPlasmodium falciparumparasites resistant to front-line antimalarial artemisinin-combination therapies (ACT) threatens to erase the considerable gains against the disease of the last decade. We developed a new large-scale phenotypic screening pipeline and used it to carry out the first large-scale forward-genetic phenotype screen inP. falciparumto identify genes that allow parasites to survive febrile temperatures.Results Screening identified more than 200P. falciparummutants with differential responses to increased temperature. These mutants were more likely to be sensitive to artemisinin derivatives as well as to heightened oxidative stress. Major processes critical forP. falciparumtolerance to febrile temperatures and artemisinin included 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 were up-regulated in response to heat shock, as were otherPlasmodiumgenes with orthologs in plant and algal genomes.Conclusions Plasmodium falciparumparasites appear to exploit their innate febrile-response mechanisms to mediate resistance to artemisinin. Both responses depend on endosymbiotic cynobacterium-related ancestral genes in the parasite’s genome, suggesting a link to the evolutionary origins ofPlasmodiumparasites in free-living ancestors. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Wang, Chengqi |e verfasserin |4 aut | |
| 700 | 1 | |a Oberstaller, Jenna |e verfasserin |4 aut | |
| 700 | 1 | |a Thomas, Phaedra |e verfasserin |4 aut | |
| 700 | 1 | |a Otto, Thomas D. |e verfasserin |4 aut | |
| 700 | 1 | |a Casandra, Debora |e verfasserin |4 aut | |
| 700 | 1 | |a Boyapalle, Sandhya |e verfasserin |4 aut | |
| 700 | 1 | |a Adapa, Swamy R. |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Shulin |e verfasserin |4 aut | |
| 700 | 1 | |a Button-Simons, Katrina |e verfasserin |4 aut | |
| 700 | 1 | |a Mayho, Matthew |e verfasserin |4 aut | |
| 700 | 1 | |a Rayner, Julian C. |e verfasserin |4 aut | |
| 700 | 1 | |a Ferdig, Michael T. |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Rays H. Y. |e verfasserin |4 aut | |
| 700 | 1 | |a Adams, John H. |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2022) vom: 04. Dez. |
| 773 | 1 | 8 | |g year:2022 |g day:04 |g month:12 |
| 856 | 4 | 0 | |u https://doi.org/10.1038/s41467-021-24814-1 |z lizenzpflichtig |3 Volltext |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2020.12.10.419788 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 912 | |a SSG-OLC-PHA | ||
| 951 | |a AR | ||
| 952 | |j 2022 |b 04 |c 12 | ||