Cell death in Leishmania induced by stress and differentiation: programmed cell death or necrosis?

Zangger, Haroun; Mottram, Jeremy C.; Fasel, Nicolás

doi:10.1038/sj.cdd.4401071

Cited by 139 publications

(132 citation statements)

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“…In line with previous observations, this phenomenon is explained by the fact that prior to Leishmania divisions, the progeny minicircles replicate and contain nicks or gaps. 46,47 These nicks and gaps are repaired upon division, however our data suggest that these nicks are detectable by TUNEL staining in stages where the parasites is preparing for division. 48 While apoptosis-like cell death plays a crucial role for population survival, also for several other protozoan parasites, it is still a matter of debate how cell death could be beneficial for a singlecell organism.…”

Section: Discussionmentioning

confidence: 58%

Apoptotic-likeLeishmaniaexploit the host´s autophagy machinery to reduce T-cell-mediated parasite elimination

et al. 2015

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Apoptosis is a well-defined cellular process in which a cell dies, characterized by cell shrinkage and DNA fragmentation. In parasites like Leishmania, the process of apoptosis-like cell death has been described. Moreover upon infection, the apoptotic-like population is essential for disease development, in part by silencing host phagocytes. Nevertheless, the exact mechanism of how apoptosis in unicellular organisms may support infectivity remains unclear. Therefore we investigated the fate of apoptotic-like Leishmania parasites in human host macrophages. Our data showed-in contrast to viable parasites-that apoptotic-like parasites enter an LC3 C , autophagy-like compartment. The compartment was found to consist of a single lipid bilayer, typical for LC3-associated phagocytosis (LAP). As LAP can provoke anti-inflammatory responses and autophagy modulates antigen presentation, we analyzed how the presence of apoptotic-like parasites affected the adaptive immune response. Macrophages infected with viable Leishmania induced proliferation of CD4 C T-cells, leading to a reduced intracellular parasite survival. Remarkably, the presence of apoptotic-like parasites in the inoculum significantly reduced T-cell proliferation. Chemical induction of autophagy in human monocyte-derived macrophage (hMDM), infected with viable parasites only, had an even stronger proliferationreducing effect, indicating that host cell autophagy and not parasite viability limits the T-cell response and enhances parasite survival. Concluding, our data suggest that apoptotic-like Leishmania hijack the host cells´autophagy machinery to reduce T-cell proliferation. Furthermore, the overall population survival is guaranteed, explaining the benefit of apoptosis-like cell death in a single-celled parasite and defining the host autophagy pathway as a potential therapeutic target in treating Leishmaniasis.

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Section: Discussionmentioning

confidence: 58%

Apoptotic-likeLeishmaniaexploit the host´s autophagy machinery to reduce T-cell-mediated parasite elimination

et al. 2015

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“…However, new findings indicate that unicellular eukaryotes exhibited a type of cell death similar to typical mammalian PCD. PCD has been described in several species including the kinetoplastids Trypanosoma cruzi (Welburn et al 1996), L. amazonensis (Moreira et al 1996) T. brucei brucei (Ridgley et al 1999), L. donovani (Lee et al 2002), L. mexicana (Zangger et al 2002), L. major (Arnoult et al 2002), the amitochondrial parasites Trichomonas vaginalis (Chose et al 2002) and Tritrichomonas foetus (Mariante et al 2003), Plasmodium falciparum (Picot et al 1997), Toxoplasma gondii (Peng et al 2003), yeast (Madeo et al 1999) and Dictyostelium (Cornillon et al 1994). However, the function of PCD in unicellular organisms is under speculation.…”

Section: Discussionmentioning

confidence: 99%

Programmed cell death in Trypanosoma cruzi induced by Bothrops jararaca venom

Deolindo

Teixeira-Ferreira

Melo

et al. 2005

Mem. Inst. Oswaldo Cruz

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Cells die through a programmed process or accidental death, know as apoptosis or necrosis, respectively. Bothrops jararaca is a snake whose venom inhibits the growth ofIn multicellular organisms, programmed cell death (PCD), also known as apoptosis, is important to control cell number for proper development and tissue homeostasis, removal of unwanted cells and functional control of the immune, haemopoietic and nervous systems (Welburn et al. 1997). The process of PCD is activated by genetically controlled cell suicide machinery (Ameisen 1996). In vertebrate cells, PCD can be activated by external stimuli (ethanol, reactive oxygen species, and receptor ligands) and internal processes (mitotic catastrophe, replication failures, developmental programmed cell death) (Fröhlich & Madeo 2000). PCD is also a common response to cell stress caused by different toxins (Vaux 2002). Independent of the stimulus, PCD usually involves alteration in the mitochondrial membrane permeability, caspase activation, phosphatidylserine (PS) exposure, nuclear and cytoplasmic condensation, DNA fragmentation and breakage of the cell into apoptotic bodies, which are engulfed by the surrounding cells (Vaux & Strasser 1996). PCD is a process found in virtually all nucleated metazoan cells, and it has been recently associated with several species of unicellular eukaryotes, notably kinetoplastids (Ameisen et al. 1995, Welburn et al. 1996, Moreira et al. 1996 (Picot et al. 1997, Peng et al. 2003, and amitochondrion parasites (Chose et al. 2002, Mariante et al. 2003.Snake venoms have been identified as the richest source of enzymes among poisonous animal, displaying a variety of biological activities (Tan & Ponnudurai 1992). Bothrops jararaca is a snake of the viperidae family, largely distributed in Brazil and responsible for 90% of the ophidian envenomations in humans (Bochner & Struchiner 2003). Trypanosoma cruzi is the agent of Chagas disease affecting 16-18 million people in Latin America. We have previously demonstrated that B. jararaca venom inhibited the growth of epimastigote forms of T. cruzi, causing mitochondrion swelling and kinetoplast disorganization (Gonçalves et al. 2002). Because of the ultrastructural alteration observed in the mitochondrion after venom treatment it was suggested that impairment of this organelle was probably responsible for growth inhibition (Gonçalves et al. 2002). However, how epimastigotes were demising was not analyzed. Thus, the aim of the present work was to identify if PCD or necrosis was being induced in T. cruzi epimastigote forms during B. jararaca venom treatment. MATERIALS AND METHODSParasite and venom -Epimastigote forms of T. cruzi (Y strain) were maintained at 28°C by weekly transfers in liver infusion tryptose (LIT) medium (Camargo 1964) supplemented with 10% fetal bovine serum (FBS). Fourday-old cultured epimastigote forms (mid-log phase) were used for the experiments. 34 34 34 3 4 Cell death by snake venom • Poliana Deolindo et al.Lyophilized B. jararaca venom was purchased from the Instit...

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“…3 The existence of apoptosis also could be useful to avoid killing by the host as suggested in the case of parasitic infection such as Leishmania donovani. 4 Protein phosphorylation plays a key role in signal transduction in eucaryotic systems. Diacylglycerol activates Ca 2 þ and phospholipid-dependent protein kinase C (PKC) that is associated with many cellular processes in mammalian cells including differentiation, hormone and neurotransmitter release, and gene activation.…”

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confidence: 99%

Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I–DNA complex

et al. 2006

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Protein kinase C (PKC) is an important constituent of the signaling pathways involved in apoptosis. We report here that like staurosporine, withaferin A is a potent inhibitor of PKC. In Leishmania donovani, the inhibition of PKC by withaferin A causes depolarization of DW m and generates ROS inside cells. Loss of DW m leads to the release of cytochrome c into the cytosol and subsequently activates caspase-like proteases and oligonucleosomal DNA cleavage. Moreover, in treated cells, oxidative DNA lesions facilitate the stabilization of topoisomerase I-mediated cleavable complexes, which also contribute to DNA fragmentation. However, withaferin A and staurosporine cannot induce cleavable complex formation in vitro with recombinant topoisomerase I nor with nuclear extracts from control cells. Taken together, our results indicate that inhibition of PKC by withaferin A is a central event for the induction of apoptosis and that the stabilization of topoisomerase I-DNA complex is necessary to amplify apoptotic process.

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Cell death in Leishmania induced by stress and differentiation: programmed cell death or necrosis?

Cited by 139 publications

References 74 publications

Apoptotic-likeLeishmaniaexploit the host´s autophagy machinery to reduce T-cell-mediated parasite elimination

Apoptotic-likeLeishmaniaexploit the host´s autophagy machinery to reduce T-cell-mediated parasite elimination

Programmed cell death in Trypanosoma cruzi induced by Bothrops jararaca venom

Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I–DNA complex

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