Artemisinin Induces Calcium-Dependent Protein Secretion in the Protozoan Parasite<i>Toxoplasma gondii</i>

Nagamune, Kisaburo; Beatty, Wandy L.; Sibley, L. David

doi:10.1128/ec.00262-07

Cited by 112 publications

(108 citation statements)

References 55 publications

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“…The inability of artemisinin to inhibit merozoite invasion was somewhat surprising given reports that this drug binds to SERCA (sarcoplasmic/endoplasmic reticulum calcium ATPase), a calcium ATPase with a role in microneme release during invasion in Toxoplasma gondii (35). In vitro binding of artemisinin to ATPase 6, the SERCA homologue in P. falciparum, has also been reported previously (36).…”

Section: Discussionmentioning

confidence: 97%

Defining the Timing of Action of Antimalarial Drugs against Plasmodium falciparum

Wilson

Langer

Goodman

et al. 2013

Antimicrob Agents Chemother

129

135

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e Most current antimalarials for treatment of clinical Plasmodium falciparum malaria fall into two broad drug families and target the food vacuole of the trophozoite stage. No antimalarials have been shown to target the brief extracellular merozoite form of blood-stage malaria. We studied a panel of 12 drugs, 10 of which have been used extensively clinically, for their invasion, schizont rupture, and growth-inhibitory activity using high-throughput flow cytometry and new approaches for the study of merozoite invasion and early intraerythrocytic development. Not surprisingly, given reported mechanisms of action, none of the drugs inhibited merozoite invasion in vitro. Pretreatment of erythrocytes with drugs suggested that halofantrine, lumefantrine, piperaquine, amodiaquine, and mefloquine diffuse into and remain within the erythrocyte and inhibit downstream growth of parasites. Studying the inhibitory activity of the drugs on intraerythrocytic development, schizont rupture, and reinvasion enabled several different inhibitory phenotypes to be defined. All drugs inhibited parasite replication when added at ring stages, but only artesunate, artemisinin, cycloheximide, and trichostatin A appeared to have substantial activity against ring stages, whereas the other drugs acted later during intraerythrocytic development. When drugs were added to late schizonts, only artemisinin, cycloheximide, and trichostatin A were able to inhibit rupture and subsequent replication. Flow cytometry proved valuable for in vitro assays of antimalarial activity, with the free merozoite population acting as a clear marker for parasite growth inhibition. These studies have important implications for further understanding the mechanisms of action of antimalarials, studying and evaluating drug resistance, and developing new antimalarials.

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Section: Discussionmentioning

confidence: 97%

Defining the Timing of Action of Antimalarial Drugs against Plasmodium falciparum

Wilson

Langer

Goodman

et al. 2013

Antimicrob Agents Chemother

129

135

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“…These results indicated that the suppressive effect of matrine on IL-2 mRNA expression in Jurkat T cells did not result from its cytotoxicity. Another compound, artemisinin derived from the medicinal herb Artemisia annua L. demonstrated its potency in anti-inflammation, immune regulation and enhancement of Ca 2ϩ flux, 13,15) and it has been used in many countries for treatment of severe and chloroquineresistant malaria. However, this compound showed no ability to induce T cell anergy (Fig.…”

Section: Validation Of T Cell Anergy Induction Model Inmentioning

confidence: 99%

Matrine Induces Cell Anergy in Human Jurkat T Cells through Modulation of Mitogen-Activated Protein Kinases and Nuclear Factor of Activated T-Cells Signaling with Concomitant Up-Regulation of Anergy-Associated Genes Expression

Wong

et al. 2010

Biological & Pharmaceutical Bulletin

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T cell activation plays a pivotal role in the pathogenesis of human autoimmune and chronic inflammatory illnesses. In the past decades, great efforts have been made to find immunosuppressants that can intervene in T cell activation and proliferation. However, in treatment of some refractory cases of these illnesses, immunosuppressants must be taken for long-term, even life-long, in spite of various side effects. Therefore, T cell immunotolerance induction leading to T cells anergy has been becoming a promising new therapeutic strategy for autoimmune conditions. Such agents typically have few side effects because they act only as adjuvants in the human body to induce T cell anergy in response to unknown antigens. In fact, T cell activation in the body requires engagement of both the T cell receptor (TCR) and CD28 on the cells through participation of the major histocompatibility complex (MHC) peptides and B7 family members on antigen presenting cells (APC). When T cells are stimulated by antigen(s) through TCR in the absence of CD28/B7, the cells develop long-term hyporesponsiveness to subsequent stimulations 1) ; this is known as T cell anergy. In other words, T cell anergy is an immunotolerance condition in which T cells are intrinsically and functionally inactivated following encounter with antigen(s); the cells remain alive but hyporesponsive for an extended period of time.2) Furthermore, this hyporesponsiveness is characterized by a suppression of interleukin (IL)-2 secretion, such that T cell activation and proliferation are in turn inhibited.1) Thus, agents that stimulate TCR alone and suppress IL-2 secretion before T cells are activated by antigen(s) are likely ideal candidates for use as T cell immunotolerance inducers.Although detailed molecular mechanisms of T cell anergy remain unclear, it is well-known that it is partially mediated through calcineurin and the nuclear factor of activated T-cells (NFAT).3) In the resting T cells, NFAT proteins are phosphorylated and reside in the cytoplasm. When the cells were stimulated, NFAT proteins are dephosphorylated by calcineurin and then translocated into the nucleus and become the transcriptional active, and thus providing a direct line between intracellular Ca 2ϩ signaling and gene expression. 4)Especially, when T cells received TCR/CD28 stimulation, NFAT will be dephosphorylated, translocated into nucleus and cooperated with AP-1, the transcriptional partner of NFAT which is composed of heterodimers of Fos-and Junfamily protein, to induce many genes encoding cytokines, chemokines and other products in the immune responses. Different from NFAT, the activators of AP-1 are mitogen-activated protein kinases (MAPKs) including c-Jun NH 2 -terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 kinase. In contrast, when NFAT was preactivated by Ca 2ϩ signals or TCR stimulation alone without co-stimulation provided by CD28 and thus in the absence of its transcriptional factor AP-1, the T cell anergy will be induced. 5)To date, the optimum and sim...

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“…Pyrimethamine inhibits the parasite's dihydrofolate reductase enzyme (11), while artemisinin appears to perturb calcium homeostasis in the parasite (27). Tgmsh-1 mutant parasites are not resistant to either of these drugs (E. M. Garrison and G. Arrizabalaga, unpublished observations).…”

mentioning

confidence: 99%

The Antibiotic Monensin Causes Cell Cycle Disruption ofToxoplasma gondiiMediated through the DNA Repair Enzyme TgMSH-1

Lavine

Arrizabalaga

2011

Antimicrob Agents Chemother

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Monensin is a polyether ionophore antibiotic that is widely used in the control of coccidia in animals. Despite its significance in veterinary medicine, little is known about its mode of action and potential mechanisms of resistance in coccidian parasites. Here we show that monensin causes accumulation of the coccidian Toxoplasma gondii at an apparent late-S-phase cell cycle checkpoint. In addition, experiments utilizing a monensinresistant T. gondii mutant show that this effect of monensin is dependent on the function of a mitochondrial homologue of the MutS DNA damage repair enzyme (TgMSH-1). Furthermore, the same TgMSH-1-dependent cell cycle disruption is observed with the antiparasitic ionophore salinomycin and the DNA alkylating agent methyl nitrosourea. Our results suggest a novel mechanism for the mode of action of monensin and salinomycin on coccidial parasites, in which the drug activates an MSH-1-dependent cell cycle checkpoint by an unknown mechanism, ultimately leading to the death of the parasite. This model would indicate that cell cycle disruption is an important mediator of drug susceptibility and resistance to ionophoric antibiotics in coccidian parasites.

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Artemisinin Induces Calcium-Dependent Protein Secretion in the Protozoan ParasiteToxoplasma gondii

Cited by 112 publications

References 55 publications

Defining the Timing of Action of Antimalarial Drugs against Plasmodium falciparum

Defining the Timing of Action of Antimalarial Drugs against Plasmodium falciparum

Matrine Induces Cell Anergy in Human Jurkat T Cells through Modulation of Mitogen-Activated Protein Kinases and Nuclear Factor of Activated T-Cells Signaling with Concomitant Up-Regulation of Anergy-Associated Genes Expression

The Antibiotic Monensin Causes Cell Cycle Disruption ofToxoplasma gondiiMediated through the DNA Repair Enzyme TgMSH-1

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