Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22340%2F18%3A43916652" target="_blank" >RIV/60461373:22340/18:43916652 - isvavai.cz</a>

Result on the web

<a href="http://www.bloodjournal.org/content/131/11/1234?sso-checked=true" target="_blank" >http://www.bloodjournal.org/content/131/11/1234?sso-checked=true</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1182/blood-2017-11-814665" target="_blank" >10.1182/blood-2017-11-814665</a>

Result language

angličtina

Original language name

Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance

Original language description

Artemisinin resistance threatens worldwide malaria control and elimination. Elevation of phosphatidylinositol-3-phosphate (PI3P) can induce resistance in blood stages of Plasmodium falciparum. The parasite unfolded protein response (UPR) has also been implicated as a proteostatic mechanism that may diminish artemisinin-induced toxic proteopathy. How PI3P acts and its connection to the UPR remain unknown, although both are conferred by mutation in P falciparum Kelch13 (K13), the marker of artemisinin resistance. Here we used cryoimmunoelectron microscopy to show that K13 concentrates at PI3P tubules/ vesicles of the parasite&apos;s endoplasmic reticulum (ER) in infected red cells. K13 colocalizes and copurifies with the major virulence adhesin PfEMP1. The PfEMP1-K13 proteome is comprehensively enriched in multiple proteostasis systems of protein export, quality control, and folding in the ER and cytoplasm and UPR. Synthetic elevation of PI3P that induces resistance in absence of K13 mutation also yields signatures of proteostasis and clinical resistance. These findings imply a key role for PI3P-vesicle amplification as a mechanism of resistance of infected red cells. As validation, the major resistance mutation K13C580Y quantitatively increased PI3P tubules/vesicles, exporting them throughout the parasite and the red cell. Chemical inhibitors and fluorescence microscopy showed that alterations in PfEMP1 export to the red cell and cytoadherence of infected cells to a host endothelial receptor are features of multiple K13 mutants. Together these data suggest that amplified PI3P vesicles disseminate widespread proteostatic capacity that may neutralize artemisinins toxic proteopathy and implicate a role for the host red cell in artemisinin resistance. The mechanistic insights generated will have an impact on malaria drug development.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

20401 - Chemical engineering (plants, products)

Project

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Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

BLOOD

ISSN

0006-4971

e-ISSN

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Volume of the periodical

131

Issue of the periodical within the volume

11

Country of publishing house

US - UNITED STATES

Number of pages

14

Pages from-to

1234-1247

UT code for WoS article

000430687500011

EID of the result in the Scopus database

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