Tumor necrosis factor reduces Plasmodium falciparum growth and activates calcium signaling in human malaria parasites

Abstract

BackgroundPlasmodium has a complex biology including the ability to interact with host signals modulating their function through cellular machinery. Tumor necrosis factor (TNF) elicits diverse cellular responses including effects in malarial pathology and increased infected erythrocyte cytoadherence. As TNF levels are raised during Plasmodium falciparum infection we have investigated whether it has an effect on the parasite asexual stage.MethodsFlow cytometry, spectrofluorimetric determinations, confocal microscopy and PCR real time quantifications were employed for characterizing TNF induced effects and membrane integrity verified by wheat germ agglutinin staining.ResultsTNF is able to decrease intracellular parasitemia, involving calcium as a second messenger of the pathway. Parasites incubated for 48 h with TNF showed reduced erythrocyte invasion. Thus, TNF induced rises in intracellular calcium concentration, which were blocked by prior addition of the purinergic receptor agonists KN62 and A438079, or interfering with intra- or extracellular calcium release by thapsigargin or EGTA (ethylene glycol tetraacetic acid). Importantly, expression of PfPCNA1 which encodes the Plasmodium falciparum Proliferating-Cell Nuclear Antigen 1, decreased after P. falciparum treatment of TNF (tumor necrosis factor) or 6-Bnz cAMP (N6-benzoyladenosine-3′,5′-cyclic monophosphate sodium salt).ConclusionsThis is potentially interesting data showing the relevance of calcium in downregulating a gene involved in cellular proliferation, triggered by TNF.General significanceThe data show that Plasmodium may subvert the immunological system and use TNF for the control of its proliferation within the vertebrate host.

Comparative 1D Blue-Native electrophoresis analysis of Plasmodium falciparum and human proteins associated with cytoadherence

“…Several groups have identified signalling pathways that are activated in host endothelium by cytoadherence, and this is reflected in the identification of classical kinases such as dual specificity tyrosine-phosphorylation-regulated kinase 2, as well as structural signalling molecules such as ezrin that act via the actin cytoskeleton and may be involved in ICAM-1 induced signalling [ 36 ]. The malaria parasite has an extensive signalling family of proteins [ 37 ] and has recently been shown to be able to respond to external stimuli [ 38 , 39 ], although not yet to cytoadherence. Several signalling proteins were identified in this study from different kinase groups (e.g.…”

GosB Inhibits Triacylglycerol Synthesis and Promotes Cell Survival in Mouse Mammary Epithelial Cells

“…Calcium is a well-known intracellular messenger that modulates many aspects of cell life [ 21 , 42 , 43 ]. Intracellular Ca 2+ accumulation activates the mitochondrial apoptotic pathway with high levels of Bax and activation of caspase-3 [ 44 – 46 ].…”

Signaling Strategies of Malaria Parasite for Its Survival, Proliferation, and Infection during Erythrocytic Stage

“…Melatonin hormone was found to induce the production of IP3 through PLC, which further opens the Ca 2+ channels in the ER (91–93). An increase in calcium level on incubation with tumor necrosis factor (TNF)-α caused the downregulation of P. falciparum’s proliferating cell nuclear antigen-1 and ultimately the retardation of parasite growth (94). Calcium mediates its activity through Pf CDPK7.…”