Gibberellin Biosynthetic Inhibitors Make Human Malaria Parasite Plasmodium falciparum Cells Swell and Rupture to Death

Malaria remains as one of the most devastating infectious disease, and continues to exact an enormous toll in medical cost and days of labor lost especially in the tropics. Effective malaria control and eventual eradication remain a huge challenge, with efficacious antimalarials as important intervention/management tool. Clearly new alternative drugs that are more affordable and with fewer side effects are desirable. After preliminary in vitro assays with plant growth regulators and inhibitors, here, we focus on biosynthetic inhibitors of gibberellin, a plant hormone with many important roles in plant growth, and show their inhibitory effect on the growth of both apicomplexa, Plasmodium falciparum and Toxoplasma gondii. Treatment of P. falciparum cultures with the gibberellin biosynthetic inhibitors resulted in marked morphological changes that can be reversed to a certain degree under hyperosmotic environment. These unique observations suggest that changes in the parasite membrane permeability may explain the pleiotropic effects observed within the intracellular parasites

Toxoplasma gondii seroprevalence in goats, cats and humans in Russia

The findings suggest that the natural environment in Russia may be widely polluted with T. gondii oocysts shed by cats, and ingestion of these oocysts provides a major route for human infection with this parasite

ATF6β is a host cellular target of the Toxoplasma gondii virulence factor ROP18

Toxoplasma virulence factor ROP18 targets endoplasmic reticulum–bound transcription factor ATF6β in the host cell, leading to the detrimental loss of ATF6β through proteasome-dependent degradation

Artemisinin Induces Calcium-Dependent Protein Secretion in the Protozoan Parasite Toxoplasma gondii▿ †

Intracellular calcium controls several crucial cellular events in apicomplexan parasites, including protein secretion, motility, and invasion into and egress from host cells. The plant compound thapsigargin inhibits the sarcoplasmic-endoplasmic reticulum calcium ATPase (SERCA), resulting in elevated calcium and induction of protein secretion in Toxoplasma gondii. Artemisinins are natural products that show potent and selective activity against parasites, making them useful for the treatment of malaria. While the mechanism of action is uncertain, previous studies have suggested that artemisinin may inhibit SERCA, thus disrupting calcium homeostasis. We cloned the single-copy gene encoding SERCA in T. gondii (TgSERCA) and demonstrate that the protein localizes to the endoplasmic reticulum in the parasite. In extracellular parasites, TgSERCA partially relocalized to the apical pole, a highly active site for regulated secretion of micronemes. TgSERCA complemented a calcium ATPase-defective yeast mutant, and this activity was inhibited by either thapsigargin or artemisinin. Treatment of T. gondii with artemisinin triggered calcium-dependent secretion of microneme proteins, similar to the SERCA inhibitor thapsigargin. Artemisinin treatment also altered intracellular calcium in parasites by increasing the periodicity of calcium oscillations and inducing recurrent, strong calcium spikes, as imaged using Fluo-4 labeling. Collectively, these results demonstrate that artemisinin perturbs calcium homeostasis in T. gondii, supporting the idea that Ca2+-ATPases are potential drug targets in parasites

Artemisinin-Resistant Mutants of Toxoplasma gondii Have Altered Calcium Homeostasis▿

Artemisinin is a plant sesquiterpene lactone that has become an important drug for combating malaria, especially in regions where resistance to other drugs is widespread. While the mechanism of action is debated, artemisinin has been reported to inhibit the sarcoplasmic endoplasmic reticulum Ca2+ ATPase (SERCA) in the malaria parasite. Artemisinin is also effective against Toxoplasma in vitro and in vivo, although it is less potent and, hence, is generally not used therapeutically to treat toxoplasmosis. To explore the mechanism of action, we generated chemically derived mutants of Toxoplasma gondii that were resistant to growth inhibition by this compound in vitro. Three artemisinin-resistant (ARTr) mutant clones that differed in their sensitivities in vitro by three- to fivefold compared with that of the wild-type parasites were obtained. ARTr mutants were cross-resistant to other derivatives of artemisinin, the most potent of which was artemisone. Resistance was not due to molecular alterations or differences in the expression of SERCA or other putative targets, such as proteins that code for multidrug resistance or translationally controlled tumor protein. ARTr mutants were resistant to the induction of protein secretion from micronemes, a calcium-dependent process that is triggered by artemisinin. ARTr mutants were not cross-resistant to secretion induced by thapsigargin but were more sensitive and were unable to regulate cytoslic calcium following treatment with this compound. These studies implicate calcium homeostasis in the mechanism of action of artemisinins against apicomplexan parasites

Surface sialic acids taken from the host allow trypanosome survival in Tsetse fly vectors

The African trypanosome Trypanosoma brucei, which causes sleeping sickness in humans and Nagana disease in livestock, is spread via blood-sucking Tsetse flies. In the fly's intestine, the trypanosomes survive digestive and trypanocidal environments, proliferate, and translocate into the salivary gland, where they become infectious to the next mammalian host. Here, we show that for successful survival in Tsetse flies, the trypanosomes use trans-sialidase to transfer sialic acids that they cannot synthesize from host's glycoconjugates to the glycosylphosphatidylinositols (GPIs), which are abundantly expressed on their surface. Trypanosomes lacking sialic acids due to a defective generation of GPI-anchored trans-sialidase could not survive in the intestine, but regained the ability to survive when sialylated by means of soluble trans-sialidase. Thus, surface sialic acids appear to protect the parasites from the digestive and trypanocidal environments in the midgut of Tsetse flies