Leishmania mexicana: Inhibition of camptothecin-induced apoptosis of monocyte-derived dendritic cells

Valdés-Reyes, Leonardo; Argueta, Jesús; Morán, Julio; Salaiza, Norma; Hernández, Juan M.; Berzunza, Miriam; Aguirre-Garcı́a, Marı́a Magdalena; Becker, Ingeborg; Gutiérrez‐Kobeh, Laila

doi:10.1016/j.exppara.2008.10.020

Cited by 29 publications

(22 citation statements)

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“…Inhibition of host‐cell apoptosis is one of the survival strategies used by intracellular pathogens 27 , 28 , 29 . L. donovani, an intra‐macrophage parasite, also exploits various mechanisms to inhibit host‐cell apoptosis 19 , 20 , 21 , 22 , 23 . To determine whether Leishmania parasite modulates PD‐1 pathway for inhibition of macrophage apoptosis, we checked the effect of L.donovani infection on macrophage apoptosis and its correlation with PD‐1 receptor.…”

Section: Resultsmentioning

confidence: 99%

“…In the present study it has been demonstrated that PD‐1/SHP2 signaling axis negatively regulates pro‐survival AKT activation in macrophages and H 2 O 2 ‐mediated PD‐1 induction contributes in macrophage apoptosis. Besides, as inhibition of macrophage apoptosis is critically important in leishmaniasis 22 , 23 , 24 , 25 , 26 and is an established paradigm of infection, therefore, modulation of death receptor PD‐1 expression during infection might have an impact in regulating host‐cell apoptosis, which also is addressed here. Our findings further shed light on the fact that L. donovani infection‐mediated downregulation of PD‐1 and subsequent dampening of PD‐1/SHP2 signaling helped the parasite in activating pro‐survival AKT pathway, which in turn led to inhibition of proapoptotic protein BAD, thereby inhibiting host‐cell apoptosis.…”

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confidence: 99%

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The role of PD‐1 in regulation of macrophage apoptosis and its subversion by Leishmania donovani

et al. 2017

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Programmed death-1 receptor (PD-1) expressed in many immune cells is known to trigger T-cell exhaustion but the significance of macrophage-associated PD-1 in relevance to macrophage apoptosis is not known. This study is aimed to delineate whether PD-1 pathway has any role in eliciting macrophage apoptosis and, if so, then how the intra-macrophage parasite, Leishmania donovani modulates PD-1 pathway for protecting its niche. Resting macrophages when treated with H2O2 showed increased PD-1 expression and apoptosis, which was further enhanced on PD-1 agonist treatment. The administration of either PD-1 receptor or PD-1 ligand-blocking antibodies reversed the process thus documenting the involvement of PD-1 in macrophage apoptosis. On the contrary, L. donovani-infected macrophages showed decreased PD-1 expression concurrent with inhibition of apoptosis. The activation of PD-1 pathway was found to negatively regulate the phosphorylation of pro-survival AKT, which was reversed during infection. Infection-induced PD-1 downregulation led to the activation of AKT resulting in phosphorylation and subsequent inhibition of proapoptotic protein BAD. Strong association of SHP2 (a SH2-containing ubiquitously expressed tyrosine-specific protein phosphatase) with PD-1 along with AKT deactivation observed in H2O2-treated macrophages was reversed by L. donovani infection. Kinetic analysis coupled with inhibitor-based approach and knockdown experiments demonstrated that L. donovani infection actively downregulated the PD-1 by deactivating NFATc1 as revealed by its reduced nuclear translocation. The study thus elucidates the detailed mechanism of the role of PD-1 in macrophage apoptosis and its negative modulation by Leishmania for their intracellular survival.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

The role of PD‐1 in regulation of macrophage apoptosis and its subversion by Leishmania donovani

et al. 2017

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“…The parasite-induced anti-apoptotic effect is associated with a significant reduction of caspase-3 activity in L. major - or L. mexicana -infected PMN [81] or monocyte-derived dendritic cells [82]. In addition, L. infantum infection affected the apoptosis of U-937 human monocytic cell line via a mechanism involving inhibition of caspase-3 activation [83].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA Expression Profile in Human Macrophages in Response to Leishmania major Infection

et al. 2013

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Background Leishmania (L.) are intracellular protozoan parasites able to survive and replicate in the hostile phagolysosomal environment of infected macrophages. They cause leishmaniasis, a heterogeneous group of worldwide-distributed affections, representing a paradigm of neglected diseases that are mainly embedded in impoverished populations. To establish successful infection and ensure their own survival, Leishmania have developed sophisticated strategies to subvert the host macrophage responses. Despite a wealth of gained crucial information, these strategies still remain poorly understood. MicroRNAs (miRNAs), an evolutionarily conserved class of endogenous 22-nucleotide non-coding RNAs, are described to participate in the regulation of almost every cellular process investigated so far. They regulate the expression of target genes both at the levels of mRNA stability and translation; changes in their expression have a profound effect on their target transcripts.Methodology/Principal FindingsWe report in this study a comprehensive analysis of miRNA expression profiles in L. major-infected human primary macrophages of three healthy donors assessed at different time-points post-infection (three to 24 h). We show that expression of 64 out of 365 analyzed miRNAs was consistently deregulated upon infection with the same trends in all donors. Among these, several are known to be induced by TLR-dependent responses. GO enrichment analysis of experimentally validated miRNA-targeted genes revealed that several pathways and molecular functions were disturbed upon parasite infection. Finally, following parasite infection, miR-210 abundance was enhanced in HIF-1α-dependent manner, though it did not contribute to inhibiting anti-apoptotic pathways through pro-apoptotic caspase-3 regulation.Conclusions/SignificanceOur data suggest that alteration in miRNA levels likely plays an important role in regulating macrophage functions following L. major infection. These results could contribute to better understanding of the dynamics of gene expression in host cells during leishmaniasis.

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“…The former mechanism is unlikely, since it has been demonstrated that Leishmania can inhibit apoptotic mechanisms in phagocytic cells [29], [30], [31], [32]. The possible benefits derived from cytotoxic CD8-induced apoptosis of the host cells infected with Leishmania could be dual: the elimination of the parasite and the expansion of the specific immune response by providing novel parasite antigens [10], as has described for M. tuberculosis [33].…”

Section: Discussionmentioning

confidence: 99%

CD8 Cells of Patients with Diffuse Cutaneous Leishmaniasis Display Functional Exhaustion: The Latter Is Reversed, In Vitro, by TLR2 Agonists

Hernández-Ruiz

Salaiza‐Suazo²,

Carrada³

et al. 2010

PLoS Negl Trop Dis

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Leishmania mexicana (Lm) causes localized (LCL) and diffuse (DCL) cutaneous leishmaniasis. DCL patients have a poor cellular immune response leading to chronicity. It has been proposed that CD8 T lymphocytes (CD8) play a crucial role in infection clearance, although the role of CD8 cytotoxicity in disease control has not been elucidated. Lesions of DCL patients have been shown to harbor low numbers of CD8, as compared to patients with LCL, and leishmanicidal treatment restores CD8 numbers. The marked response of CD8 towards Leishmania parasites led us to analyze possible functional differences between CD8 from patients with LCL and DCL. We compared IFNγ production, antigen-specific proliferation, and cytotoxicity of CD8 purified from PBMC against autologous macrophages (MO) infected with Leishmania mexicana (MOi). Additionally, we analyzed tissue biopsies from both groups of patients for evidence of cytotoxicity associated with apoptotic cells in the lesions. We found that CD8 cell of DCL patients exhibited low cytotoxicity, low antigen-specific proliferation and low IFNγ production when stimulated with MOi, as compared to LCL patients. Additionally, DCL patients had significantly less TUNEL+ cells in their lesions. These characteristics are similar to cellular “exhaustion” described in chronic infections. We intended to restore the functional capacity of CD8 cells of DCL patients by preincubating them with TLR2 agonists: Lm lipophosphoglycan (LPG) or Pam3Cys. Cytotoxicity against MOi, antigen-specific proliferation and IFNγ production were restored with both stimuli, whereas PD-1 (a molecule associated with cellular exhaustion) expression, was reduced. Our work suggests that CD8 response is associated with control of Lm infection in LCL patients and that chronic infection in DCL patients leads to a state of CD8 functional exhaustion, which could facilitate disease spread. This is the first report that shows the presence of functionally exhausted CD8 T lymphocytes in DCL patients and, additionally, that pre-stimulation with TLR2 ligands can restore the effector mechanisms of CD8 T lymphocytes from DCL patients against Leishmania mexicana-infected macrophages.

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Leishmania mexicana: Inhibition of camptothecin-induced apoptosis of monocyte-derived dendritic cells

Cited by 29 publications

References 35 publications

The role of PD‐1 in regulation of macrophage apoptosis and its subversion by Leishmania donovani

The role of PD‐1 in regulation of macrophage apoptosis and its subversion by Leishmania donovani

MicroRNA Expression Profile in Human Macrophages in Response to Leishmania major Infection

CD8 Cells of Patients with Diffuse Cutaneous Leishmaniasis Display Functional Exhaustion: The Latter Is Reversed, In Vitro, by TLR2 Agonists

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