Programmed Cell Death during Malaria Parasite Infection of the Vertebrate Host and Mosquito Vector

Baton, Luke Anthony; Warr, Emma; Hoffman, Seth A; Dimopoulos, George

doi:10.1007/978-0-387-76717-8_7

Cited by 4 publications

(6 citation statements)

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“…With respect to unicellular eukaryotes, trying to shoehorn observations into classifications designed for multicellular organisms is clearly not the way forward. Some form of non-necrotic death is taking place in these organisms but, although outward signs are similar, molecular pathways clearly differ as homologues of apoptosis-inducing factors and effector caspases regulating apoptosis in metazoans have not been found [ 17 ]. The evolution of cell suicide mechanisms evidently predates the metazoans [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…These organisms include two much studied models, the yeast Saccharomyces cerevisiae [ 3 ] and the slime mould, Dictyostelium discoideum [ 4 ]. Amongst the parasitic protists, the trypanosomatids have been the focus of most research on PCD [ 5 - 11 ], but PCD features have also been recorded in; Toxoplasma gondii [ 12 ]; Blastocystis hominis [ 13 ]; in protozoans that do not possess mitochondria such as Giardia intestinalis, Trichomonas foetus and T. vaginalis [ 14 , 15 ] ; and in P. berghei and P. falciparum [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…Few studies have so far been made of PCD in Plasmodium spp. and the majority of these have focussed on the erythrocytic stages of the human malaria, P. falciparum , where conflicting observations and conclusions have been made [ 2 , 17 , 22 ]. The occurrence of apoptosis-like cell death has also been disputed in the rodent malaria P. berghei .…”

Section: Introductionmentioning

confidence: 99%

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Malaria ookinetes exhibit multiple markers for apoptosis-like programmed cell death in vitro

et al. 2009

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Background: A wide range of unicellular eukaryotes have now been shown to undergo a form of programmed cell death (PCD) that resembles apoptosis; exhibiting morphological and, in some cases, biochemical markers typical of metazoans. However, reports that sexual and asexual stages of malaria parasites exhibit these markers have been challenged. Here we use a rodent malaria model, Plasmodium berghei, to determine whether, and what proportion of cultured ookinetes show signs of apoptosis-like death and extend the study to examine ookinetes of Plasmodium falciparum in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Malaria ookinetes exhibit multiple markers for apoptosis-like programmed cell death in vitro

et al. 2009

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“…Markers of apoptosis have been described in both the vertebrate and vector stages of the malaria parasite [14] – [17] although, as discussed by Arambage and colleagues [18] , conflicting results have emerged from different laboratories, particularly regarding apoptosis in erythrocytic stages. In the mosquito midgut lumen, motile zygotes or ookinetes are formed around 18 h post-infection and move out of the blood meal bolus before traversing the midgut epithelium to form oocysts beneath the basal lamina.…”

Section: Introductionmentioning

confidence: 99%

Naturally Occurring Triggers that Induce Apoptosis-Like Programmed Cell Death in Plasmodium berghei Ookinetes

et al. 2010

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Several protozoan parasites have been shown to undergo a form of programmed cell death that exhibits morphological features associated with metazoan apoptosis. These include the rodent malaria parasite, Plasmodium berghei. Malaria zygotes develop in the mosquito midgut lumen, forming motile ookinetes. Up to 50% of these exhibit phenotypic markers of apoptosis; as do those grown in culture. We hypothesised that naturally occurring signals induce many ookinetes to undergo apoptosis before midgut traversal. To determine whether nitric oxide and reactive oxygen species act as such triggers, ookinetes were cultured with donors of these molecules. Exposure to the nitric oxide donor SNP induced a significant increase in ookinetes with condensed nuclear chromatin, activated caspase-like molecules and translocation of phosphatidylserine that was dose and time related. Results from an assay that detects the potential-dependent accumulation of aggregates of JC-1 in mitochondria suggested that nitric oxide does not operate via loss of mitochondrial membrane potential. L-DOPA (reactive oxygen species donor) also caused apoptosis in a dose and time dependent manner. Removal of white blood cells significantly decreased ookinetes exhibiting a marker of apoptosis in vitro. Inhibition of the activity of nitric oxide synthase in the mosquito midgut epithelium using L-NAME significantly decreased the proportion of apoptotic ookinetes and increased the number of oocysts that developed. Introduction of a nitric oxide donor into the blood meal had no effect on mosquito longevity but did reduce prevalence and intensity of infection. Thus, nitric oxide and reactive oxygen species are triggers of apoptosis in Plasmodium ookinetes. They occur naturally in the mosquito midgut lumen, sourced from infected blood and mosquito tissue. Up regulation of mosquito nitric oxide synthase activity has potential as a transmission blocking strategy.

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“…In metazoans, apoptosis represents a programmed form of cell death that plays a distinctive role in tissue development and homeostasis in response to an internal physiological disturbance [15] . However, apoptosis in unicellular organisms is thought to represent an altruistic behavior where a part of population which is less competent or non-viable is eliminated for the successful survival and onward transmission of the more competent organisms [16] , [17] . So far, PCD has been described in diverse protozoan parasites including Leishmania [18] , Trypanasoma [19] , Giardia [20] , in the ciliated protozoan Tetrahymena thermophila [21] , Entamoeba histolytica [22] , Blastocystis hominis [23] and Plasmodia [24] – [26] .…”

Section: Introductionmentioning

confidence: 99%

Resistance of a Rodent Malaria Parasite to a Thymidylate Synthase Inhibitor Induces an Apoptotic Parasite Death and Imposes a Huge Cost of Fitness

et al. 2011

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BackgroundThe greatest impediment to effective malaria control is drug resistance in Plasmodium falciparum, and thus understanding how resistance impacts on the parasite's fitness and pathogenicity may aid in malaria control strategy.Methodology/Principal FindingsTo generate resistance, P. berghei NK65 was subjected to 5-fluoroorotate (FOA, an inhibitor of thymidylate synthase, TS) pressure in mice. After 15 generations of drug pressure, the 2% DT (the delay time for proliferation of parasites to 2% parasitaemia, relative to untreated wild-type controls) reduced from 8 days to 4, equalling the controls. Drug sensitivity studies confirmed that FOA-resistance was stable. During serial passaging in the absence of drug, resistant parasite maintained low growth rates (parasitaemia, 15.5%±2.9, 7 dpi) relative to the wild-type (45.6%±8.4), translating into resistance cost of fitness of 66.0%. The resistant parasite showed an apoptosis-like death, as confirmed by light and transmission electron microscopy and corroborated by oligonucleosomal DNA fragmentation.Conclusions/SignificanceThe resistant parasite was less fit than the wild-type, which implies that in the absence of drug pressure in the field, the wild-type alleles may expand and allow drugs withdrawn due to resistance to be reintroduced. FOA resistance led to depleted dTTP pools, causing thymineless parasite death via apoptosis. This supports the tenet that unicellular eukaryotes, like metazoans, also undergo apoptosis. This is the first report where resistance to a chemical stimulus and not the stimulus itself is shown to induce apoptosis in a unicellular parasite. This finding is relevant in cancer therapy, since thymineless cell death induced by resistance to TS-inhibitors can further be optimized via inhibition of pyrimidine salvage enzymes, thus providing a synergistic impact. We conclude that since apoptosis is a process that can be pharmacologically modulated, the parasite's apoptotic machinery may be exploited as a novel drug target in malaria and other protozoan diseases of medical importance.

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Programmed Cell Death during Malaria Parasite Infection of the Vertebrate Host and Mosquito Vector

Cited by 4 publications

References 118 publications

Malaria ookinetes exhibit multiple markers for apoptosis-like programmed cell death in vitro

Malaria ookinetes exhibit multiple markers for apoptosis-like programmed cell death in vitro

Naturally Occurring Triggers that Induce Apoptosis-Like Programmed Cell Death in Plasmodium berghei Ookinetes

Resistance of a Rodent Malaria Parasite to a Thymidylate Synthase Inhibitor Induces an Apoptotic Parasite Death and Imposes a Huge Cost of Fitness

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