Syk inhibitors interfere with erythrocyte membrane modification during P falciparum growth and suppress parasite egress

Antonella Pantaleo, Kristina R. Kesely, Maria Carmina Pau, Ioannis Tsamesidis, Evelin Schwarzer, Oleksii A. Skorokhod, Huynh D. Chien, Marta Ponzi, Lucia Bertuccini, Philip S. Low, Francesco M. Turrini

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Band 3 (also known as the anion exchanger, SLCA1, AE1) constitutes the major attachment site of the spectrin-based cytoskeleton to the erythrocyte's lipid bilayer and thereby contributes critically to the stability of the red cell membrane. During the intraerythrocytic stage of Plasmodium falciparum's lifecycle, band 3 becomes tyrosine phosphorylated in response to oxidative stress, leading to a decrease in its affinity for the spectrin/actin cytoskeleton and causing global membrane destabilization. Because this membrane weakening is hypothesized to facilitate parasite egress and the consequent dissemination of released merozoites throughout the bloodstream,wedecided to explore which tyrosine kinase inhibitors might block the kinase-induced membrane destabilization. We demonstrate here that multiple Syk kinase inhibitors both prevent parasiteinduced band 3 tyrosine phosphorylation and inhibit parasite-promoted membrane destabilization. We also show that the same Syk kinase inhibitors suppress merozoite egress near the end of the parasite's intraerythrocytic lifecycle. Because the entrapped merozoites die when prevented from escaping their host erythrocytes and because some Syk inhibitors have displayed long-term safety in human clinical trials, we suggest Syk kinase inhibitors constitute a promising class of antimalarial drugs that can suppress parasitemia by inhibiting a host target that cannot be mutated by the parasite to evolve drug resistance.

Original languageEnglish
Pages (from-to)1031-1040
Number of pages10
JournalBlood
Volume130
Issue number8
DOIs
Publication statusPublished - Aug 24 2017

Fingerprint

Erythrocyte Membrane
Merozoites
Parasites
Phosphotransferases
Membranes
Spectrin
Growth
Erythrocyte Anion Exchange Protein 1
Phosphorylation
Lipid bilayers
Oxidative stress
Parasitemia
Antimalarials
Lipid Bilayers
Cell membranes
Plasmodium falciparum
Actin Cytoskeleton
Drug Resistance
Protein-Tyrosine Kinases
Actins

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Pantaleo, A., Kesely, K. R., Pau, M. C., Tsamesidis, I., Schwarzer, E., Skorokhod, O. A., ... Turrini, F. M. (2017). Syk inhibitors interfere with erythrocyte membrane modification during P falciparum growth and suppress parasite egress. Blood, 130(8), 1031-1040. https://doi.org/10.1182/blood-2016-11-748053

Syk inhibitors interfere with erythrocyte membrane modification during P falciparum growth and suppress parasite egress. / Pantaleo, Antonella; Kesely, Kristina R.; Pau, Maria Carmina; Tsamesidis, Ioannis; Schwarzer, Evelin; Skorokhod, Oleksii A.; Chien, Huynh D.; Ponzi, Marta; Bertuccini, Lucia; Low, Philip S.; Turrini, Francesco M.

In: Blood, Vol. 130, No. 8, 24.08.2017, p. 1031-1040.

Research output: Contribution to journalArticle

Pantaleo, A, Kesely, KR, Pau, MC, Tsamesidis, I, Schwarzer, E, Skorokhod, OA, Chien, HD, Ponzi, M, Bertuccini, L, Low, PS & Turrini, FM 2017, 'Syk inhibitors interfere with erythrocyte membrane modification during P falciparum growth and suppress parasite egress', Blood, vol. 130, no. 8, pp. 1031-1040. https://doi.org/10.1182/blood-2016-11-748053
Pantaleo A, Kesely KR, Pau MC, Tsamesidis I, Schwarzer E, Skorokhod OA et al. Syk inhibitors interfere with erythrocyte membrane modification during P falciparum growth and suppress parasite egress. Blood. 2017 Aug 24;130(8):1031-1040. https://doi.org/10.1182/blood-2016-11-748053
Pantaleo, Antonella ; Kesely, Kristina R. ; Pau, Maria Carmina ; Tsamesidis, Ioannis ; Schwarzer, Evelin ; Skorokhod, Oleksii A. ; Chien, Huynh D. ; Ponzi, Marta ; Bertuccini, Lucia ; Low, Philip S. ; Turrini, Francesco M. / Syk inhibitors interfere with erythrocyte membrane modification during P falciparum growth and suppress parasite egress. In: Blood. 2017 ; Vol. 130, No. 8. pp. 1031-1040.
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