Abstract
Apoptosis and other types of regulated cell death have been defined as fundamental processes in plant and animal development, but the occurrence of, and possible roles for, regulated cell death in parasitic protozoa remain controversial. A key problem has been the difficulty in reconciling the presence of apparent morphological markers of apoptosis and the notable absence of some of the key executioners functioning in higher eukaryotes. Here, we review the evidence for regulated cell death pathways in selected parasitic protozoa and propose that cell death in these organisms be classified into just two primary types: necrosis and incidental death. It is our opinion that dedicated molecular machinery required for the initiation and execution of regulated cell death has yet to be convincingly identified.
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References
Galluzzi, L. et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 19, 107–120 (2012).
Nagata, S., Hanayama, R. & Kawane, K. Autoimmunity and the clearance of dead cells. Cell 140, 619–630 (2010).
Tait, S. W. G. & Green, D. R. Mitochondria and cell death: outer membrane permeabilization and beyond. Nature Rev. Mol. Cell Biol. 11, 621–632 (2010).
Fuentes-Prior, P. & Salvesen, G. S. The protein structures that shape caspase activity, specificity, activation and inhibition. Biochem. J. 384, 201–232 (2004).
Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8, 445–544 (2012).
Yang, Z. & Klionsky, D. J. An overview of the molecular mechanism of autophagy. Curr. Top. Microbiol. Immunol. 335, 1–32 (2009).
Kroemer, G. et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 16, 3–11 (2009).
Vandenabeele, P., Galluzzi, L., Vanden Berghe, T. & Kroemer, G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nature Rev. Mol. Cell Biol. 11, 700–714 (2010).
Galluzzi, L. et al. Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes. Cell Death Differ. 16, 1093–1107 (2009).
Welburn, S. C., Dale, C., Ellis, D., Beecroft, R. & Pearson, T. W. Apoptosis in procyclic Trypanosoma brucei rhodesiense in vitro. Cell Death Differ. 3, 229–236 (1996).
Ameisen, J. C. et al. Apoptosis in a unicellular eukaryote (Trypanosoma cruzi): implications for the evolutionary origin and role of programmed cell death in the control of cell proliferation, differentiation and survival. Cell Death Differ. 2, 285–300 (1996).
Jimenez-Ruiz, A. et al. Apoptotic markers in protozoan parasites. Parasit. Vectors 3, 104 (2010).
Gannavaram, S. & Debrabant, A. Programmed cell death in Leishmania: biochemical evidence and role in parasite infectivity. Front. Cell. Infect. Microbiol. 2, 1–9 (2012).
Reece, S. E., Pollitt, L. C., Colegrave, N. & Gardner, A. The meaning of death: evolution and ecology of apoptosis in protozoan parasites. PLoS Pathog. 7, e1002320 (2011).
Matthews, K. R. Controlling and coordinating development in vector-transmitted parasites. Science 331, 1149–1153 (2011).
Debrabant, A., Lee, N., Bertholet, S., Duncan, R. & Nakhasi, H. L. Programmed cell death in trypanosomatids and other unicellular organisms. Int. J. Parasitol. 33, 257–267 (2003).
Nguewa, P. A., Fuertes, M. A., Valladares, B., Alonso, C. & Perez, J. M. Programmed cell death in trypanosomatids: a way to maximize their biological fitness? Trends Parasitol. 20, 375–380 (2004).
Hurd, H. & Carter, V. The role of programmed cell death in Plasmodium-mosquito interactions. Int. J. Parasitol. 34, 1459–1472 (2004).
Welburn, S. C., Macleod, E., Figarella, K. & Duzensko, M. Programmed cell death in African trypanosomes. Parasitology 132, (Suppl. 1) S7–S18 (2006).
Van Zandbergen, G., Luder, C. G., Heussler, V. & Duszenko, M. Programmed cell death in unicellular parasites: a prerequisite for sustained infection? Trends Parasitol. 26, 477–483 (2010).
MacGregor, P., Szoor, B., Savill, N. J. & Matthews, K. R. Trypanosomal immune evasion, chronicity and transmission: an elegant balancing act. Nature Rev. Microbiol. 10, 431–438 (2012).
Aslam, N. & Turner, C. M. R. The relationship of variable antigen expression and population growth rates in Trypanosoma brucei. Parasitol. Res. 78, 661–664 (1992).
Macgregor, P., Savill, N. J., Hall, D. & Matthews, K. R. Transmission stages dominate trypanosome within-host dynamics during chronic infections. Cell Host Microbe 9, 310–318 (2011).
Vassella, E., Reuner, B., Yutzy, B. & Boshart, M. Differentiation of African trypanosomes is controlled by a density sensing mechanism which signals cell cycle arrest via the cAMP pathway. J. Cell Sci. 110, 2661–2671 (1997).
Titus, R. G. & Ribeiro, J. M. Salivary gland lysates from the sand fly Lutzomyia longipalpis enhance Leishmania infectivity. Science 239, 1306–1308 (1988).
Rogers, M. E., Ilg, T., Nikolaev, A. V., Ferguson, M. A. & Bates, P. A. Transmission of cutaneous leishmaniasis by sand flies is enhanced by regurgitation of fPPG. Nature 430, 463–467 (2004).
van Zandbergen, G. et al. Leishmania disease development depends on the presence of apoptotic promastigotes in the virulent inoculum. Proc. Natl Acad. Sci. USA 103, 13837–13842 (2006).
Wanderley, J. L. et al. Cooperation between apoptotic and viable metacyclics enhances the pathogenesis of leishmaniasis. PLoS ONE 4, e5733 (2009).
de Freitas Balanco, J. M. et al. Apoptotic mimicry by an obligate intracellular parasite downregulates macrophage microbicidal activity. Curr. Biol. 11, 1870–1873 (2001).
Wanderley, J. L., Moreira, M. E., Benjamin, A., Bonomo, A. C. & Barcinski, M. A. Mimicry of apoptotic cells by exposing phosphatidylserine participates in the establishment of amastigotes of Leishmania (L) amazonensis in mammalian hosts. J. Immunol. 176, 1834–1839 (2006).
Jensen, J. B., Boland, M. T. & Akood, M. Induction of crisis forms in cultured Plasmodium falciparum with human immune serum from Sudan. Science 216, 1230–1233 (1982).
Al-Olayan, E. M., Williams, G. T. & Hurd, H. Apoptosis in the malaria protozoan, Plasmodium berghei: a possible mechanism for limiting intensity of infection in the mosquito. Int. J. Parasitol. 32, 1133–1143 (2002).
Luder, C., Campos-Salinas, J., Gonzalez-Rey, E. & van Zandbergen, G. Impact of protozoan cell death on parasite-host interactions and pathogenesis. Parasit. Vectors 3, 116 (2010).
Kaczanowski, S., Sajid, M. & Reece, S. Evolution of apoptosis-like programmed cell death in unicellular protozoan parasites. Parasit. Vectors 4, 44 (2011).
Lee, N. et al. Programmed cell death in the unicellular protozoan parasite Leishmania. Cell Death Differ. 9, 53–64 (2002).
Le, C. L., Sinden, R. E. & Dessens, J. T. The role of metacaspase 1 in Plasmodium berghei development and apoptosis. Mol. Biochem. Parasitol. 153, 41–47 (2007).
Porter, H., Gamette, M. J., Cortes-Hernandez, D. G. & Jensen, J. B. Asexual blood stages of Plasmodium falciparum exhibit signs of secondary necrosis, but not classical apoptosis after exposure to febrile temperature (40 C). J. Parasitol. 94, 473–480 (2008).
Totino, P. R. et al. Apoptosis of non-parasitized red blood cells in malaria: a putative mechanism involved in the pathogenesis of anaemia. Malar. J. 9, 350 (2010).
Worthen, C., Jensen, B. C. & Parsons, M. Diverse effects on mitochondrial and nuclear functions elicited by drugs and genetic knockdowns in bloodstream stage Trypanosoma brucei. PLoS Negl. Trop. Dis. 4, e678 (2010).
Engelbrecht, D., Durand, P. M. & Coetzer, T. L. On programmed cell death in Plasmodium falciparum: status quo. J. Trop. Med. 2012, 646534 (2012).
Figarella, K. et al. Prostaglandin D2 induces programmed cell death in Trypanosoma brucei bloodstream form. Cell Death Differ. 12, 335–346 (2005).
Goldshmidt, H. et al. Persistent ER stress induces the spliced leader RNA silencing pathway (SLS), leading to programmed cell death in Trypanosoma brucei. PLoS Pathog. 6, e1000731 (2010).
Lustig, Y. et al. Spliced-leader RNA silencing: a novel stress-induced mechanism in Trypanosoma brucei. EMBO Rep. 8, 408–413 (2007).
Uren, G. A. et al. Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma. Mol. Cell 6, 961–967 (2000).
Coll, N. S. et al. Arabidopsis type I metacaspases control cell death. Science 330, 1393–1397 (2010).
Tsiatsiani, L. et al. Metacaspases. Cell Death Differ. 18, 1279–1288 (2011).
Helms, M. J. et al. Bloodstream form Trypanosoma brucei depend upon multiple metacaspases associated with RAB11-positive endosomes. J. Cell Sci. 119, 1105–1117 (2006).
Lee, N., Gannavaram, S., Selvapandiyan, A. & Debrabant, A. Characterization of metacaspases with trypsin-like activity and their putative role in programmed cell death in the protozoan parasite Leishmania. Eukaryot. Cell 6, 1745–1757 (2007).
Zalila, H. et al. Processing of metacaspase into a cytoplasmic catalytic domain mediating cell death in Leishmania major. Mol. Microbiol. 79, 222–239 (2011).
Castanys-Muñoz, E., Brown, E., Coombs, G. H. & Mottram, J. C. Leishmania mexicana metacaspase is a negative regulator of amastigote proliferation in mammalian cells. Cell Death Dis. 3, e385 (2012).
Zangger, H., Mottram, J. C. & Fasel, N. Cell death in Leishmania induced by stress and differentiation: programmed cell death or necrosis? Cell Death Differ. 9, 1126–1139 (2002).
El-Fadili, A. K. et al. Cathepsin B-like and cell death in the unicellular human pathogen Leishmania. Cell Death Dis. 1, e71 (2010).
Boya, P. & Kroemer, G. Lysosomal membrane permeabilization in cell death. Oncogene 27, 6434–6451 (2008).
Duszenko, M. et al. Autophagy in protists. Autophagy 7, 127–158 (2011).
Besteiro, S., Williams, R. A. M., Morrison, L. S., Coombs, G. H. & Mottram, J. C. Endosome sorting and autophagy are essential for differentiation and virulence of Leishmania major. J. Biol. Chem. 281, 11384–11396 (2006).
Williams, R. A. M., Tetley, L., Mottram, J. C. & Coombs, G. H. Cysteine peptidases CPA and CPB are vital for autophagy and differentiation in Leishmania mexicana. Mol. Microbiol. 61, 655–674 (2006).
Williams, R. A. M., Smith, T. K., Cull, B., Mottram, J. C. & Coombs, G. H. ATG5 is essential for ATG8-dependent autophagy and mitochondrial homeostasis in Leishmania. PLoS Pathog. 8, e1002695 (2012).
Besteiro, S., Brooks, C. F., Striepen, B. & Dubremetz, J. F. Autophagy protein Atg3 is essential for maintaining mitochondrial integrity and for normal intracellular development of Toxoplasma gondii tachyzoites. PLoS Pathog. 7, e1002416 (2011).
Li, F. J. et al. A role of autophagy in Trypanosoma brucei cell death. Cell. Microbiol. 14, 1242–1256 (2012).
Alvarez, V. E. et al. Autophagy is involved in nutritional stress response and differentiation in Trypanosoma cruzi. J. Biol. Chem. 283, 3454–3464 (2008).
Bera, A., Singh, S., Nagaraj, R. & Vaidya, T. Induction of autophagic cell death in Leishmania donovani by antimicrobial peptides. Mol. Biochem. Parasitol. 127, 23–35 (2003).
Totino, P. R. R., Daniel-Ribeiro, C. T., Corte-Real, S. & de Fatima Ferreira-da-Cruz, M. Plasmodium falciparum: erythrocytic stages die by autophagic-like cell death under drug pressure. Exp. Parasitol. 118, 478–486 (2008).
Uzcategui, N. L. et al. Antiproliferative effect of dihydroxyacetone on Trypanosoma brucei bloodstream forms: cell cycle progression, subcellular alterations and cell death. Antimicrob. Agents Chemother. 51, 3960–3968 (2007).
Delgado, M., Anderson, P., Garcia-Salcedo, J. A., Caro, M. & Gonzalez-Rey, E. Neuropeptides kill African trypanosomes by targeting intracellular compartments and inducing autophagic-like cell death. Cell Death Differ. 16, 406–416 (2008).
Shen, S., Kepp, O. & Kroemer, G. The end of autophagic cell death? Autophagy 8, 1–3 (2012).
Denton, D., Nicolson, S. & Kumar, S. Cell death by autophagy: facts and apparent artefacts. Cell Death Differ. 19, 87–95 (2012).
Ghosh, D., Walton, J. L., Roepe, P. D. & Sinai, A. P. Autophagy is a cell death mechanism in Toxoplasma gondii. Cell. Microbiol. 14, 589–607 (2012).
Dacks, J. B., Walker, G. & Field, M. C. Implications of the new eukaryotic systematics for parasitologists. Parasitol. Int. 57, 97–104 (2008).
Weingartner, A. et al. Leishmania promastigotes lack phosphatidylserine but bind annexin V upon permeabilization or miltefosine treatment. PLoS ONE 7, e42070 (2012).
McLuskey, K. et al. Crystal structure of a Trypanosoma brucei metacaspase. Proc. Natl Acad. Sci. USA 109, 7469–7474 (2012).
Moss, C. X., Westrop, G. D., Juliano, L., Coombs, G. H. & Mottram, J. C. Metacaspase 2 of Trypanosoma brucei is a calcium-dependent cysteine peptidase active without processing. FEBS Lett. 581, 5635–5639 (2007).
Acknowledgements
The authors are grateful to N. Fasel for insightful comments on the manuscript and K. McLuskey for help with preparing the figure in box 2. J.C.M. and G.H.C. are supported by the UK Medical Research Council (grant 0700127). The Wellcome Trust Centre for Molecular Parasitology is supported by core funding from the Wellcome Trust (grant 085349).
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Proto, W., Coombs, G. & Mottram, J. Cell death in parasitic protozoa: regulated or incidental?. Nat Rev Microbiol 11, 58–66 (2013). https://doi.org/10.1038/nrmicro2929
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DOI: https://doi.org/10.1038/nrmicro2929
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