Apoptosis and apoptotic mimicry: the Leishmania connection

Wanderley, João Luiz Mendes; Barcinski, Marcello A.

doi:10.1007/s00018-010-0291-0

Cited by 41 publications

(35 citation statements)

References 66 publications

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“…Various reports state that parasites use "apoptotic mimicry" in order to silence phagocytes enabling survival. 44,45 By applying unified criteria of the Nomenclature Committee on Cell Death, we could define a subpopulation of the Leishmania infectious inoculum to show characteristics of apoptosis. Interestingly, viable parasites, residing in the G 2 phase, also were shown to be positive for TUNEL staining, a finding which could be misinterpreted as apoptotic mimicry.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

et al. 2015

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“…In many models of apoptosis, a collapse in the electrochemical gradient across the mitochondrial membrane is a key indicator of the initiation of programmed cell death (7,36,40,50). JC-1 is a unique fluorescent cationic dye that fluoresces red upon aggregation within intact, negatively charged mitochondria.…”

Section: Resultsmentioning

confidence: 99%

Efficacy of Synthetic Peptides RP-1 and AA-RP-1 against Leishmania Species In Vitro and In Vivo

Erfe

David

Huang

et al. 2012

Antimicrob Agents Chemother

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Host defense peptides are naturally occurring molecules that play essential roles in innate immunity to infection. Based on prior structure-function knowledge, we tested two synthetic peptides (RP-1 and AA-RP-1) modeled on the conserved, microbicidal ␣-helical domain of mammalian CXCL4 platelet kinocidins. These peptides were evaluated for efficacy against Leishmania species, the causative agents of the group of diseases known as leishmaniasis. In vitro antileishmanial activity was assessed against three distinct Leishmania strains by measuring proliferation, metabolic activity and parasite viability after exposure to various concentrations of peptides. We demonstrate that micromolar concentrations of RP-1 and AA-RP-1 caused dose-dependent growth inhibition of Leishmania promastigotes. This antileishmanial activity correlated with rapid membrane disruption, as well as with a loss of mitochondrial transmembrane potential. In addition, RP-1 and AA-RP-1 demonstrated distinct and significant in vivo antileishmanial activities in a mouse model of experimental visceral leishmaniasis after intravenous administration. These results establish efficacy of RP-1 lineage synthetic peptides against Leishmania species in vitro and after intravenous administration in vivo and provide further validation of proof of concept for the development of these and related systemic antiinfective peptides targeting pathogens that are resistant to conventional antibiotics.

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“…This strategy relies on the presence of PS on the virus surface to mimic apoptotic debris. Thereby these viruses take advantage of the host cell's PS-dependent apoptotic removal system for internalization [35]. First suggested for hepatitis B virus [36], and subsequently demonstrated experimentally for VV MVs [13], PSmediated macropinocytosis has now been shown to be used by lentiviral vectors, pichinde virus (a model for Lassa fever virus), cytomegaloviruses, Ebola virus, Marburg virus, and possibly HIV-1 [37 ,38-40].…”

Section: Apoptotic Mimicrymentioning

confidence: 99%