Inhibition of dendritic cell apoptosis by Leishmania mexicana amastigotes

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.

Leishmania mexicana amastigotes inhibit p38 and JNK and activate PI3K/AKT: role in the inhibition of apoptosis of dendritic cells

“…Figure b shows the mean ± SD of three independent experiments. We have previously demonstrated that the infection of moDC with L. mexicana amastigotes diminishes camptothecin‐induced DNA fragmentation . Taking this result in account, in this work we inhibited p38 and JNK in moDC previously to the infection with L. mexicana amastigotes and treatment with camptothecin in order to determine the participation of p38 and JNK in the fragmentation of DNA.…”

“…One cell‐mediated defense mechanism that Leishmania affects in behalf of its survival is apoptosis. It has been widely described that Leishmania inhibits apoptosis in various cell types including macrophages , monocytes , neutrophils and dendritic cells . Nevertheless, the pathways that are targeted by the parasite to achieve the anti apoptotic effect have not been fully addressed.…”

“…moDC were subjected to different treatments: (i) infection with L. mexicana amastigotes (10 : 1 parasite : cell ratio). This is the ratio we have used previously and has proven to be effective due to the fact that dendritic cells phagocytic capacity is limited as compared with that of macrophages ; (ii) treatment with the pro‐apoptotic agent camptothecin (10 μ m ) (Sigma). Camptothecin was chosen because is a good inducer of apoptosis, both in dividing and nondividing cells, and is an S‐phase‐specific anticancer agent that can also induce apoptosis independent of DNA synthesis ; (iii) infection with L. mexicana amastigotes (10 : 1 parasite : cell ratio) and treatment with 10 μ m camptothecin.…”

Leishmania donovani infection drives the priming of human monocyte‐derived dendritic cells during Plasmodium falciparum co‐infections

“…Conversely, an intrinsic ability to delay apoptosis induction in various cell subsets, including macrophages, mo‐DCs and polymorphonuclear neutrophil granulocytes, has been described for promastigotes and amastigotes of several Leishmania spp. , supporting the speculation that the Leishmania parasite may deliberately manipulate host cell apoptotic machinery to improve its survival and pathogenicity. This activity, however, arose when cells were challenged with a pathogen multiplicity equal to or lower than 10 parasites per cell, disregarding the potential cytotoxic effect that higher parasite numbers may display.…”

Nuevas estrategias para el tratamiento de la leishmaniasis: mecanismo de acción de lípidos antitumorales, interacción hospedero-parásito, y su posible utilidad terapéutica

“…Estos resultados coinciden con observaciones previas, en las cuales la infección con promastigotes de L. major, L. donovani o L. amazonensis inhibe la apoptosis en macrófagos y otras células hospederas (131-133, 207, 236). La infección con promastigotes de L. major inhibe la apoptosis espontánea de los neutrófilos (207), y la infección con promastigotes y amastigotes de L. mexicana inhibe la apoptosis de células dendríticas (135,136). Se sabe que los neutrófilos son reclutados al sitio de la infección y estos son muy eficientes para internalizar parásitos.…”