Features of Apoptosis in<i>Plasmodium falciparum</i>Erythrocytic Stage through a Putative Role of PfMCA1 Metacaspase‐Like Protein

Meslin, Benoît; Barnadas, Céline; Boni, V.; Latour, Christine; Monbrison, Frédérique de; Kaiser, Karine; Picot, Stéphane

doi:10.1086/518253

Cited by 96 publications

(134 citation statements)

References 43 publications

Supporting

Mentioning

121

Contrasting

Unclassified

Order By: Relevance

“…In the case of Gb, the corresponding human cytolytic fusion protein proteolytically cleaves certain caspases to induce apoptosis (34). Comparably, P. falciparum bears one designated metacaspase, P. falciparum MCA-1 (35), which may be the target of Gb. Another hypothesis is that Gb induces eryptosis in infected erythrocytes and thus kills the parasite (7).…”

Section: Figmentioning

confidence: 99%

Antimalarial Activity of Granzyme B and Its Targeted Delivery by a Granzyme B–Single-Chain Fv Fusion Protein

Kapelski

Almeida

Fischer

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

We present here the first evidence that granzyme B acts against Plasmodium falciparum (50% inhibitory concentration [IC 50 ], 1,590 nM; 95% confidence interval [95% CI], 1,197 to 2,112 nM). We created a novel antimalarial fusion protein consisting of granzyme B fused to a merozoite surface protein 4 (MSP4)-specific single-chain Fv protein (scFv), which targets the enzyme to infected erythrocytes, with up to an 8-fold reduction in the IC 50 (176 nM; 95% CI, 154 to 202 nM). This study confirms the therapeutic efficacies of recombinant antibody-mediated antimalarial immunotherapeutics based on granzyme B. Malaria is caused by parasites of the genus Plasmodium and remains one of the most widespread and dangerous infectious diseases, causing ϳ627,000 deaths worldwide per year (1). Among the six species that infect humans, Plasmodium falciparum causes the severest form of the disease (2). There is no effective vaccine against these parasites (3, 4), and resistances are emerging against a wide variety of antimalarial drugs (5). It was recently shown in vitro that natural killer (NK) cells can eliminate erythrocytes infected with P. falciparum (6) and that this is associated with the production of the serine protease granzyme B (Gb) (7). In vivo, NK cells are essential for protection against plasmodial infections in mice (8), and increased levels of circulating Gb are found in naturally infected humans (9).We therefore investigated the antimalarial effect of recombinant Gb on P. falciparum (strain 3D7A) in a standardized 72-h drug susceptibility assay starting with synchronized ring-stage parasites (10). Gb was produced in HEK293 cells with an N-terminal protective peptide fused to an enterokinase cleavage site (EGb) to suppress the enzymatic activity in the host cells, as previously described (11). Activity was restored by the enzymatic removal of this peptide using 0.02 U of recombinant enterokinase (Novagen; Merck) per g of protein (12). The restored enzymatic activity was confirmed using a colorimetric activity assay (13). Parasite growth was specifically inhibited by activated Gb, with a half-maximal inhibitory concentration (IC 50 ) of 1,590 nM (95% confidence interval [95% CI], 1,197 to 2,112 nM, calculated using the Hill equation in GraphPad Prism version 5). Undigested (inactive) EGb showed no inhibition ( Fig. 1 and Table 1). To our knowledge, this is the first time that the antimalarial activity of Gb has been directly confirmed in vitro.We developed a strategy to target Gb to the parasite and thus reduce the required dose. Targeted toxin delivery via the parasite transferrin receptor has already been reported (14,15). Although some authors claim to have identified and characterized this receptor (16, 17), others argue that iron uptake by the parasite is nonspecific and that the P. falciparum transferrin receptor remains elusive (18). Promising alternative targets include the merozoite surface proteins (MSPs), especially MSP1, MSP2, MSP4, and MSP8, which bear glycosylphosphatidylinositol (GPI) anchors and th...

show abstract

Section: Figmentioning

confidence: 99%

Antimalarial Activity of Granzyme B and Its Targeted Delivery by a Granzyme B–Single-Chain Fv Fusion Protein

Kapelski

Almeida

Fischer

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…It is of particular interest that, in our hands, pca1 deletion alleviates lipotoxic cell death only in minimal medium. This, however, adds S. pombe to the expanding list of eukaryotes in which metacaspases are implicated in the regulation of cell death, including Arabidopsis thaliana (He et al, 2008), budding yeast (Madeo et al, 2002), and the protozoa Leishmania donovani (Lee et al, 2007) and Plasmodium falciparum (Meslin et al, 2007). Functional dualism has been described for a number of death regulators in yeast, including nuclease Nuc1, which is involved in mitochondrial-DNA recombination, and mitochondrial-fission protein Dnm1, suggesting the evolutionary sophistication of gene functions Cheng et al, 2006).…”

Section: Many Ways To Diementioning

confidence: 99%

Caspase-dependent and -independent lipotoxic cell-death pathways in fission yeast

Low

Shui

Liew

et al. 2008

Journal of Cell Science

View full text Add to dashboard Cite

Understanding the mechanisms underlying lipid-induced cell death has significant implications in both cell biology and human diseases. Previously, we showed that fission-yeast Schizosaccharomyces pombe cells deficient in triacylglycerol synthesis display apoptotic markers upon entry into stationary phase. Here, we characterize the sequential molecular events that take place at the onset of cell death in S. pombe, including a surge of diacylglycerol, post-mitotic arrest, alterations in mitochondrial activities and in intracellular redox balance, chromatin condensation, nuclear-envelope fragmentation, and eventually plasma-membrane permeabilization. Our results demonstrated active roles of mitochondria and reactive oxygen species in cell death, and identified novel cell-death regulators – including metacaspase Pca1, BH3-domain protein Rad9, and diacylglycerol-binding proteins Pck1 and Bzz1. Most importantly, we show that, under different conditions and stimuli, failure to maintain intracellular-lipid homeostasis can lead to cell death with different phenotypic manifestations, genetic criteria and cellular mechanisms, pointing to the existence of multiple lipotoxic pathways in this organism. Our study represents the first in-depth analysis of cell-death pathways in S. pombe.

show abstract

“…Etoposide treatment of P. falciparum blood-stage parasites promoted cleavage of both nuclear and apicoplast DNA (Weissig et al 1997). In addition, treatment of asexual stages of P. falciparum parasites with etoposide resulted in chromosomal cleavage at a single locus (Kelly et al 2006) as well as the induction of an apoptosis-like cell death process (Meslin et al 2007). …”

Section: Introductionmentioning

confidence: 99%

DNA topoisomerases in apicomplexan parasites: promising targets for drug discovery

et al. 2010

View full text Add to dashboard Cite

The phylum Apicomplexa includes a large group of protozoan parasites responsible for a wide range of animal and human diseases. Destructive pathogens, such as Plasmodium falciparum and Plasmodium vivax, causative agents of human malaria, Cryptosporidium parvum, responsible of childhood diarrhoea, and Toxoplasma gondii, responsible for miscarriages and abortions in humans, are frequently associated with HIV immunosuppression in AIDS patients. The lack of effective vaccines, along with years of increasing pressure to eradicate outbreaks with the use of drugs, has favoured the formation of multidrug resistant strains in endemic areas. Almost all apicomplexan of medical interest contain two endosymbiotic organelles that contain their own mitochondrial and apicoplast DNA. Apicoplast is an attractive target for drug testing because in addition to harbouring singular metabolic pathways absent in the host, it also has its own transcription and translation machinery of bacterial origin. Accordingly, apicomplexan protozoa contain an interesting mixture of enzymes to unwind DNA from eukaryotic and prokaryotic origins. On the one hand, the main mechanism of DNA unwinding includes the scission of one-type I-or both DNA strands-type II eukaryotic topoisomerases, establishing transient covalent bonds with the scissile end. These enzymes are targeted by camptothecin and etoposide, respectively, two natural drugs whose semisynthetic derivatives are currently used in cancer chemotherapy. On the other hand, DNA gyrase is a bacterial-borne type II DNA topoisomerase that operates within the apicoplast and is effectively targeted by bacterial antibiotics like fluoroquinolones and aminocoumarins. The present review is an update on the new findings concerning topoisomerases in apicomplexan parasites and the role of these enzymes as targets for therapeutic agents.

show abstract

Features of Apoptosis inPlasmodium falciparumErythrocytic Stage through a Putative Role of PfMCA1 Metacaspase‐Like Protein

Cited by 96 publications

References 43 publications

Antimalarial Activity of Granzyme B and Its Targeted Delivery by a Granzyme B–Single-Chain Fv Fusion Protein

Antimalarial Activity of Granzyme B and Its Targeted Delivery by a Granzyme B–Single-Chain Fv Fusion Protein

Caspase-dependent and -independent lipotoxic cell-death pathways in fission yeast

DNA topoisomerases in apicomplexan parasites: promising targets for drug discovery

Contact Info

Product

Resources

About