Death of a trypanosome: a selfish altruism

Duszenko, Michael; Figarella, Katherine; MacLeod, Ewan T.; Welburn, Susan C.

doi:10.1016/j.pt.2006.08.010

Cited by 109 publications

(118 citation statements)

References 67 publications

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“…These include nonparasitic organisms such as the slime mould Dictyostelium discoideum (Cornillon et al, 1994), the dinoflagellate Peridinium gatunenese (Vardi et al, 1999) and the ciliate Tetrahymena thermophila (Christensen et al, 1998a, b). In parasitic organisms, PCD has been described for kinetoplastid parasites of the genera Trypanosoma and Leishmania (Shaha, 2006;Duszenko et al, 2006), Giardia lamblia (Chose et al, 2003), Blastocystis hominis (Nasirudeen et al, 2004), Trichomonas vaginalis (Chose et al, 2002) and Plasmodium falciparum (Picot et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Hydrogen peroxide induces apoptosis-like death in Entamoeba histolytica trophozoites

et al. 2010

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Programmed cell death (PCD) is an essential process in the growth and development of multicellular organisms. However, accumulating evidence indicates that unicellular eukaryotes can also undergo PCD with apoptosis-like features. This study demonstrates that after exposure to 0.8 mM H 2 O 2 for 9 h Entamoeba histolytica presents morphological and biochemical evidence of apoptosis-like death. Morphological characteristics of apoptosis-like death including DNA fragmentation, increased vacuolization, nuclear condensation and cell rounding were observed for H 2 O 2 -exposed trophozoites with preservation of membrane integrity. Biochemical alteration in ion fluxes is also a key feature in PCD, and H 2 O 2 -exposed trophozoites showed overproduction of reactive oxygen species, increased cytosolic Ca 2+ and decreased intracellular pH.Phosphatidylserine was also found to be expressed in the outer leaflet of the plasma membrane of the H 2 O 2 -treated trophozoites. Pretreatment with the cysteine protease inhibitor E-64d, the extracellular and intracellular Ca 2+ chelators EGTA and BAPTA/AM, and the Ca 2+ influx inhibitor verapamil prior to H 2 O 2 exposure abolished DNA fragmentation. The oxidatively stressed trophozoites also showed an increased calpain activity, indicating involvement of Ca 2+ -dependent calpain-like cysteine proteases in PCD of E. histolytica. A homogeneous caspase assay showed no significant caspase activity, and administration of caspase 1 inhibitor also did not prevent the death phenotype for the oxidatively stressed trophozoites, indicating a caspaseindependent apoptosis-like death. Our observations clearly demonstrate that there is a distinct calpain-dependent but caspase-independent pathway for apoptosis-like death in oxidatively stressed E. histolytica trophozoites.

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Section: Introductionmentioning

confidence: 99%

Hydrogen peroxide induces apoptosis-like death in Entamoeba histolytica trophozoites

et al. 2010

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“…Furthermore, apoptosis in parasitic protozoa appears as a pivotal instrument of population density control to ensure a controlled and persistent parasitic load, and guarantee the survival of the host, at least until the transmission of the parasite to the next host is assured. 13 Thus, apoptosis in protozoa has been described as 'selfish altruism', 13 the organisms interacting as complex communities and not as individual entities.…”

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confidence: 99%

“…Many triggering events have been identified (see Duszenko et al 13 for a review), but apoptosis mechanisms remain largely unknown in these organisms. For example, caspases, the central executioners of metazoan apoptosis, have not been detected to date in these divergent organisms.…”

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confidence: 99%

Inhibition of active nuclear transport is an intrinsic trigger of programmed cell death in trypanosomatids

et al. 2008

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The link between nucleocytoplasmic transport and apoptosis remains controversial. Nucleocytoplasmic exchange of molecules seems indeed essential for the initiation and execution of the apoptotic programme; but inhibition of nuclear transport factors may also represent a powerful apoptotic trigger. The GTPase Ran (together with its partners), first discovered to be essential in nucleocytoplasmic transport, has multiple key functions in cell biology, and particularly in spindle assembly, kinetochore function and nuclear envelope assembly. Among the Ran partners studied, NTF2 appears to be solely involved in nucleocytoplasmic transport. Here, we localised Ran and several of its partners, RanBP1, CAS and NTF2, at the nuclear membrane in the trypanosomatid Leishmania major. Remarkably, these proteins fused to GFP decorated a perinuclear 'collar' of about 15 dots, colocalising at nuclear pore complexes with the homologue of nucleoporin Sec13. In the other trypanosomatid Trypanosoma brucei, RNAi knockdown of the expression of the corresponding genes resulted in an apoptosis-like phenomenon. These phenotypes show that Ran and its partners have a key function in trypanosomatids like they have in mammals. Our data, notably those about TbNTF2 RNAi, support the idea that active nucleocytoplasmic transport is not essential for the initiation and execution of apoptosis, and, rather, the impairment of this transport constitutes an intrinsic signal for triggering PCD.

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“…To identify the cell death mechanisms triggered by MB17, MB19, and MB38, we first investigated the morphological and biochemical changes of epimastigote cells. Programmed cell death (PCD) is characterized by the exposure of phosphatidylserine on the extracellular face of the cytoplasmic membrane, whereas classical necrosis is characterized by plasma membrane permeabilization (25)(26)(27). Parasites treated with various concentrations of MB17, MB19, and MB38 (corresponding to the IC 50 and IC 80 values) were incubated with annexin V-Alexa 647 to assess the external exposure of phosphatidylserine (a feature of PCD) and with propidium iodide to assess plasma membrane permeabilization (a feature of classical necrosis).…”

Section: Mb17 Mb19mentioning

confidence: 99%

An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells

Girard

Crispim

Stolić

et al. 2016

Antimicrob Agents Chemother

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dTrypanosoma cruzi is the etiological agent of Chagas disease, affecting approximately 10 million people in the Americas and with some 40 million people at risk. The objective of this study was to evaluate the anti-T. cruzi activity of three new diamidines that have a 3,4-ethylenedioxy extension of the thiophene core, designated MB17, MB19, and MB38. All three diamidines exhibited dose-dependent inhibition of epimastigote replication. The mechanisms of action of these diamidines were investigated. Unlike MB17 and MB19, MB38 exhibited a significant increase in the number of annexin-propidium iodide double-labeled cells compared to levels in control parasites. As MB17 had shown a lower 50% inhibitory concentration (IC 50 ) against epimastigote growth, the mechanism of action of this drug was studied in more detail. MB17 triggered a decrease in the intracellular ATP levels. As a consequence, MB17 affected the genomic DNA and kinetoplast DNA (kDNA) and impaired the parasite cell cycle. Moreover, MB17 caused DNA fragmentation, with a more severe effect on kDNA than on nuclear DNA, resulting in dyskinetoplastic cells. MB17 was tested for toxicity and effectiveness for the treatment of infected CHO-K 1 cells, exhibiting a 50% cytotoxic concentration (CC 50 ) of 13.47 ؎ 0.37 M and an IC 50 of 0.14 ؎ 0.12 M against trypomastigote release. MB17 also diminished the infection index by 60% at 0.5 M. In conclusion, despite belonging to the same family, these diamidines have different efficiencies. To summarize, MB17 was the most potent of these diamidines against epimastigotes, producing DNA damage preferentially in kDNA, impairing the parasite cell cycle, and decreasing the infection index and trypomastigote release from infected mammalian host cells, with a high selectivity index (SI) (<90). These data suggest that MB17 could be an interesting lead compound against T. cruzi. A merican trypanosomiasis, or Chagas disease, affects approximately 10 million people, with 40 million people at risk of acquiring the infection. Chagas disease is endemic to South and Central America and the southern states of the United States. Currently, it is also spreading in Europe and the rest of North America due to the immigration of infected people, as well as through transmission of the disease by transfusions, transplants, and congenital mechanisms (1, 2). The disease is caused by the protozoan Trypanosoma cruzi, which shares some distinctive features with other trypanosomes, such as the presence of a flagellum and of a kinetoplast, a complex structure bearing the mitochondrial genome. In this case, the mitochondrial genomic DNA is referred to as kinetoplast DNA, or kDNA. It consists of a great number of relaxed circular DNA molecules interlocked with each other to form a catenated DNA network (3). T. cruzi has a complex life cycle, which occurs within invertebrate and vertebrate hosts (4-6). Chagas disease presents two clinical phases, the acute phase, which appears shortly after infection and is characterized by an evident parasitemia and ...

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Death of a trypanosome: a selfish altruism

Cited by 109 publications

References 67 publications

Hydrogen peroxide induces apoptosis-like death in Entamoeba histolytica trophozoites

Hydrogen peroxide induces apoptosis-like death in Entamoeba histolytica trophozoites

Inhibition of active nuclear transport is an intrinsic trigger of programmed cell death in trypanosomatids

An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells

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