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Inducing controlled cell cycle arrest and re-entry during asexual proliferation of Plasmodium falciparum malaria parasites
The life cycle of the malaria parasite Plasmodium falciparum is tightly regulated, oscillating between stages of intense proliferation and quiescence. Cyclic 48-hour asexual replication of Plasmodium is markedly different from cell division in higher eukaryotes, and mechanistically poorly understood...
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Published in: | Scientific reports 2018-11, Vol.8 (1), p.16581-14, Article 16581 |
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Main Authors: | , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | The life cycle of the malaria parasite
Plasmodium falciparum
is tightly regulated, oscillating between stages of intense proliferation and quiescence. Cyclic 48-hour asexual replication of
Plasmodium
is markedly different from cell division in higher eukaryotes, and mechanistically poorly understood. Here, we report tight synchronisation of malaria parasites during the early phases of the cell cycle by exposure to DL-α-difluoromethylornithine (DFMO), which results in the depletion of polyamines. This induces an inescapable cell cycle arrest in G
1
(~15 hours post-invasion) by blocking G
1
/S transition. Cell cycle-arrested parasites enter a quiescent G
0
-like state but, upon addition of exogenous polyamines, re-initiate their cell cycle. This ability to halt malaria parasites at a specific point in their cell cycle, and to subsequently trigger re-entry into the cell cycle, provides a valuable framework to investigate cell cycle regulation in these parasites. We subsequently used gene expression analyses to show that re-entry into the cell cycle involves expression of Ca
2+
-sensitive (
cdpk4
and
pk2)
and mitotic kinases (
nima
and
ark2)
, with deregulation of the pre-replicative complex associated with expression of
pk2
. Changes in gene expression could be driven through transcription factors MYB1 and two ApiAP2 family members. This new approach to parasite synchronisation therefore expands our currently limited toolkit to investigate cell cycle regulation in malaria parasites. |
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ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/s41598-018-34964-w |