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

Souvik Bhattacharjee, Isabelle Coppens, Alassane Mbengue, Niraja Suresh, Mehdi Ghorbal, Zdenek Slouka, Innocent Safeukui, Hsin Yao Tang, David W. Speicher, Robert Stahelin, Narla Mohandas, Kasturi Haldar

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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’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.

Original languageEnglish (US)
Pages (from-to)1234-1247
Number of pages14
JournalBlood
Volume131
Issue number11
DOIs
StatePublished - Mar 15 2018

Fingerprint

Malaria
Amplification
Parasites
Cells
Unfolded Protein Response
Poisons
Endoplasmic Reticulum
Mutation
Malaria control
Artemisinins
Proteins
Fluorescence microscopy
Proteome
Plasmodium falciparum
phosphatidylinositol 3-phosphate
artemisinine
Fluorescence Microscopy
Quality Control
Quality control
Virulence

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Bhattacharjee, S., Coppens, I., Mbengue, A., Suresh, N., Ghorbal, M., Slouka, Z., ... Haldar, K. (2018). Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance. Blood, 131(11), 1234-1247. https://doi.org/10.1182/blood-2017-11-814665

Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance. / Bhattacharjee, Souvik; Coppens, Isabelle; Mbengue, Alassane; Suresh, Niraja; Ghorbal, Mehdi; Slouka, Zdenek; Safeukui, Innocent; Tang, Hsin Yao; Speicher, David W.; Stahelin, Robert; Mohandas, Narla; Haldar, Kasturi.

In: Blood, Vol. 131, No. 11, 15.03.2018, p. 1234-1247.

Research output: Contribution to journalArticle

Bhattacharjee, S, Coppens, I, Mbengue, A, Suresh, N, Ghorbal, M, Slouka, Z, Safeukui, I, Tang, HY, Speicher, DW, Stahelin, R, Mohandas, N & Haldar, K 2018, 'Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance', Blood, vol. 131, no. 11, pp. 1234-1247. https://doi.org/10.1182/blood-2017-11-814665
Bhattacharjee, Souvik ; Coppens, Isabelle ; Mbengue, Alassane ; Suresh, Niraja ; Ghorbal, Mehdi ; Slouka, Zdenek ; Safeukui, Innocent ; Tang, Hsin Yao ; Speicher, David W. ; Stahelin, Robert ; Mohandas, Narla ; Haldar, Kasturi. / Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance. In: Blood. 2018 ; Vol. 131, No. 11. pp. 1234-1247.
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