Abstract
According to the World Health Organization (WHO), Plasmodium falciparum is the deadliest parasite among all species. This parasite possesses the ability to sense molecules, including melatonin (MEL) and cAMP, and modulate its cell cycle accordingly. MEL synchronizes the development of this malaria parasite by activating several cascades, including the generation of the second messenger cAMP. Therefore, we performed RNA sequencing (RNA-Seq) analysis in P. falciparum erythrocytic stages (ring, trophozoite and schizont) treated with MEL and cAMP. To investigate the expression profile of P. falciparum genes regulated by MEL and cAMP, we performed RNA-Seq analysis in three P. falciparum strains (control, 3D7; protein kinase 7 knockout, PfPK7-; and PfPK7 complement, PfPK7C). In the 3D7 strain, 38 genes were differentially expressed upon MEL treatment; however, none of the genes in the trophozoite (T) stage PfPK7- knockout parasites were differentially expressed upon MEL treatment for 5 hours compared to untreated controls, suggesting that PfPK7 may be involved in the signaling leading to differential gene expression. Moreover, we found that MEL modified the mRNA expression of genes encoding membrane proteins, zinc ion-binding proteins and nucleic acid-binding proteins, which might influence numerous functions in the parasite. The RNA-Seq data following treatment with cAMP show that this molecule modulates different genes throughout the intraerythrocytic cycle, namely, 75, 101 and 141 genes, respectively, in the ring (R), T and schizont (S) stages. Our results highlight P. falciparum's perception of the external milieu through the signaling molecules MEL and cAMP, which are able to drive to changes in gene expression in the parasite.
Highlights
Malaria is a major cause of death worldwide, and Plasmodium falciparum is the species responsible for the majority of malaria cases
The results revealed that incubation of P. falciparum-infected cells with MEL for 5 hours led to considerable changes in gene expression in the 3D7 strain compared to that of the control
We previously reported that a subset of genes related to the ubiquitin proteasome system (UPS) was modulated in P. falciparum after 5 hours of treatment with MEL [6]
Summary
Malaria is a major cause of death worldwide, and Plasmodium falciparum is the species responsible for the majority of malaria cases. Our previous work showed that the host circadian rhythm, which is regulated by www.impactjournals.com/Genes&Cancer melatonin (MEL), a molecule produced by the pineal gland in response to darkness [1], plays an important role in controlling proliferation and synchronizing the development of the malaria parasite [2, 3]. This regulation is achieved by activating signaling cascades, including the PLC-IP3 pathway; cross-talking; and generating the second messengers cAMP and IP3, which elicit an increase in cytosolic calcium. The protein kinase 7 (PK7) knockout strain PfPK7 is unable to respond to MEL and to synchronize the intraerythrocytic forms of the parasites [6]
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