Abstract
Macrophages (Mφ) and dendritic cells are the major target cell populations of the obligate intracellular parasite Leishmania. Inhibition of host cell apoptosis is a strategy employed by multiple pathogens to ensure their survival in the infected cell. Leishmania promastigotes have been shown to protect Mφ, neutrophils, and dendritic cells from both natural and induced apoptosis. Nevertheless, the effect of the infection with Leishmania amastigotes in the apoptosis of these cell populations has not been established, which results are very important since amastigotes persist in cells for many days and are responsible for sustaining infection in the host. As shown in this study, apoptosis of monocyte-derived dendritic cells (moDC) induced by treatment with camptothecin was downregulated by infection with L. mexicana amastigotes from 42.48 to 36.92 % as detected by Annexin-V binding to phosphatidylserine. Also, the infection of moDC with L. mexicana amastigotes diminished the fragmentation of DNA as detected by terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick end labeling assay, and changes in cell morphology were analyzed by electron microscopy. The observed antiapoptotic effect was found to be associated with an 80 % reduction in the presence of active caspase-3 in infected moDC. The capacity of L. mexicana amastigotes to delay apoptosis induction in the infected moDC may have implications for Leishmania pathogenesis by favoring the invasion of its host and the persistence of the parasite in the infected cells.
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References
Aga E, Katschinski DM, van Zandbergen G, Laufs H, Hansen B, Müller K, Solbach W, Laskay T (2002) Inhibition of the spontaneous apoptosis of neutrophil granulocytes by the intracellular parasite Leishmania major. J Immunol 169:898–905
Akarid K, Arnoult D, Micic-Polianski J, Sif J, Estaquier J, Ameisen JC (2004) Leishmania major-mediated prevention of programmed cell death induction in infected macrophages is associated with the repression of mitochondrial release of cytochrome c. J Leukoc Biol 76:95–103
Barry M, Bleackley RC (2002) Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol 2:401–409
Bates PA, Robertson CD, Tetley L, Coombs GH (1992) Axenic cultivation and characterization of Leishmania mexicana amastigote-like forms. Parasitology 105:193–202
Carmen JC, Sinai AP (2007) Suicide prevention: disruption of apoptotic pathways by protozoan parasites. Mol Microbiol 64:904–916
Colmenares M, Corbi AL, Turco SJ, Rivas L (2004) The dendritic cell receptor DC-SIGN discriminates among species and life cycle forms of Leishmania. J Immunol 172:1186–1190
Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219
Donovan MJ, Maciuba BZ, Mahan CE, McDowell MA (2009) Leishmania infection inhibits cycloheximide-induced macrophage apoptosis in a strain-dependent manner. Exp Parasitol 123:58–64
Earnshaw WC, Martins LM, Kaufmann SH (1999) Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 68:383–424
Gao LY, Kwaik YA (2000) The modulation of host cell apoptosis by intracellular bacterial pathogens. Trends Microbiol 8:306–313
Gorczyca W, Gong J, Darzynkiewicz Z (1993) Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick translation assays. Cancer Res 53:1945–1951
Green DR (2003) Overview: apoptotic signaling pathways in the immune system. Immunol Rev 193:5–9
Green DR (2005) Apoptotic pathways: ten minutes to dead. Cell 121:671–674
Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309–1312
Hart DT, Vickerman K, Coombs GH (1981) A quick, simple method for purifying Leishmania mexicana amastigotes in large numbers. Parasitology 82:345–355
Kane MM, Mosser DM (2000) Leishmania parasites and their ploys to disrupt macrophage activation. Curr Opin Hematol 7:26–31
Lisi S, Sisto M, Acquafredda A, Spinelli R, Schiavone MA, Mitolo V, Brandonisio O, Panaro MA (2005) Infection with Leishmania infantum inhibits actinomycin D-induced apoptosis of human monocytic cell line U-937. J Eukaryot Microbiol 52:211–217
Martinou JC, Green DR (2001) Breaking the mitochondrial barrier. Nat Rev Mol Cell Biol 2:63–67
Moore KJ, Matlashewski G (1994) Intracellular infection by Leishmania donovani inhibits macrophage apoptosis. J Immunol 152:2930–2937
Moore KJ, Turco SJ, Matlashewski G (1994) Leishmania donovani infection enhances macrophage viability in the absence of exogenous growth factor. J Leukoc Biol 55:91–98
Morris EJ, Geller HM (1996) Induction of neuronal apoptosis by camptothecin, an inhibitor of DNA topoisomerase-I: evidence for cell cycle-independent toxicity. J Cell Biol 134:757–770
Mosser DM, Edelson PJ (1985) The mouse macrophage receptor for C3bi (CR3) is a major mechanism in the phagocytosis of Leishmania promastigotes. J Immunol 135:2785–2789
Naderer T, Vince JE, McConville MJ (2004) Surface determinants of Leishmania parasites and their role in infectivity in the mammalian host. Curr Mol Med 4:649–665
Nagata S (1997) Apoptosis by death factor. Cell 88:355–365
Pham NK, Mouriz J, Kima PE (2005) Leishmania pifanoi amastigotes avoid macrophage production of superoxide by inducing heme degradation. Infect Immun 73:8322–8333
Rittig MG, Bogdan C (2000) Leishmania-host-cell interaction: complexities and alternative views. Parasitol Today 16:292–297
Romani N, Gruner S, Brang D, Kämpgen E, Lenz A, Trockenbacher B, Konwalinka G, Fritsch PO, Steinman RM, Schuler G (1994) Proliferating dendritic cell progenitors in human blood. J Exp Med 180:83–93
Roulston A, Marcellus RC, Branton PE (1999) Viruses and apoptosis. Annu Rev Microbiol 53:577–628
Ruhland A, Leal N, Kima PE (2007) Leishmania promastigotes activate PI3K/Akt signalling to confer host cell resistance to apoptosis. Cell Microbiol 9:84–96
Sallusto F, Lanzavecchia A (1994) Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 179:1109–1118
Sanders EJ, Wride MA (1996) Ultrastructural identification of apoptotic nuclei using the TUNEL technique. Histochem J 28:275–281
Schaumburg F, Hippe D, Vutova P, Luder CG (2006) Pro- and anti-apoptotic activities of protozoan parasites. Parasitology 132(Suppl):S69–S85
Sinai AP, Payne TM, Carmen JC, Hardi L, Watson SJ, Molestina RE (2004) Mechanisms underlying the manipulation of host apoptotic pathways by Toxoplasma gondii. Int J Parasitol 34:381–391
Solbach W, Laskay T (2000) The host response to Leishmania infection. Adv Immunol 74:275–317
Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281:1312–1316
Valdes-Reyes L, Argueta J, Moran J, Salaiza N, Hernandez J, Berzunza M, Aguirre-Garcia M, Becker I, Gutierrez-Kobeh L (2009) Leishmania mexicana: inhibition of camptothecin-induced apoptosis of monocyte-derived dendritic cells. Exp Parasitol 121:199–207
van Zandbergen G, Klinger M, Mueller A, Dannenberg S, Gebert A, Solbach W, Laskay T (2004) Cutting edge: neutrophil granulocyte serves as a vector for Leishmania entry into macrophages. J Immunol 173:6521–6525
Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730
Woelbing F, Kostka SL, Moelle K, Belkaid Y, Sunderkoetter C, Verbeek S, Waisman A, Nigg AP, Knop J, Udey MC, von Stebut E (2006) Uptake of Leishmania major by dendritic cells is mediated by Fcgamma receptors and facilitates acquisition of protective immunity. J Exp Med 203:177–188
Yang Z, Mosser DM, Zhang X (2007) Activation of the MAPK, ERK, following Leishmania amazonensis infection of macrophages. J Immunol 178:1077–1085
Acknowledgments
Eleané de Oyarzabal was recipient of a scholarship from DGAPA, UNAM project number IN211510. This work was supported by grants IN211510 from DGAPA-UNAM and 79996 from CONACyT.
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Gutiérrez-Kobeh, L., de Oyarzabal, E., Argueta, J. et al. Inhibition of dendritic cell apoptosis by Leishmania mexicana amastigotes. Parasitol Res 112, 1755–1762 (2013). https://doi.org/10.1007/s00436-013-3334-2
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DOI: https://doi.org/10.1007/s00436-013-3334-2