Leishmania–macrophage interactions: Insights into the redox biology

Assche, Tim Van; Deschacht, Maartje; Luz, Raquel A. InocÃancio da; Maes, Louis; Cos, Paul

doi:10.1016/j.freeradbiomed.2011.05.011

Cited by 204 publications

(148 citation statements)

References 203 publications

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“…Being an intracellular parasite, Leishmania is exposed to oxidative stress throughout its mammalian life cycle, starting from its entry inside macrophages and continuing throughout its residence inside the phagolysosomal compartment (30,31). During the early stages of infection, the parasites have to combat ROS generated by the respiratory burst of macrophages for successful invasion (32).…”

Section: Donovani Promastigotes (Uns) (B) or With Promastigotes Preinmentioning

confidence: 99%

Phosphorylation of Translation Initiation Factor 2-Alpha in Leishmania donovani under Stress Is Necessary for Parasite Survival

Abhishek

Sardar

Das

et al. 2017

Molecular and Cellular Biology

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The transformation of Leishmania donovani from a promastigote to an amastigote during mammalian host infection displays the immense adaptability of the parasite to survival under stress. Induction of translation initiation factor 2-alpha (eIF2␣) phosphorylation by stress-specific eIF2␣ kinases is the basic stress-perceiving signal in eukaryotes to counter stress. Here, we demonstrate that elevated temperature and acidic pH induce the phosphorylation of Leishmania donovani eIF2␣ (LdeIF2␣). In vitro inhibition experiments suggest that interference of LdeIF2␣ phosphorylation under conditions of elevated temperature and acidic pH debilitates parasite differentiation and reduces parasite viability (P Ͻ 0.05). Furthermore, inhibition of LdeIF2␣ phosphorylation significantly reduced the infection rate (P Ͻ 0.05), emphasizing its deciding role in successful invasion and infection establishment. Notably, our findings suggested the phosphorylation of LdeIF2␣ under H 2 O 2 -induced oxidative stress. Inhibition of H 2 O 2 -induced LdeIF2␣ phosphorylation hampered antioxidant balance by impaired redox homeostasis gene expression, resulting in increased reactive oxygen species accumulation (P Ͻ 0.05) and finally leading to decreased parasite viability (P Ͻ 0.05). Interestingly, exposure to sodium antimony glucamate and amphotericin B induces LdeIF2␣ phosphorylation, indicating its possible contribution to protection against antileishmanial drugs in common use. Overall, the results strongly suggest that stress-induced LdeIF2␣ phosphorylation is a necessary event for the parasite life cycle under stressed conditions for survival.

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Section: Donovani Promastigotes (Uns) (B) or With Promastigotes Preinmentioning

confidence: 99%

Phosphorylation of Translation Initiation Factor 2-Alpha in Leishmania donovani under Stress Is Necessary for Parasite Survival

Abhishek

Sardar

Das

et al. 2017

Molecular and Cellular Biology

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“…Leishmania survives and replicates by inhibiting the oxidative burst or increasing antioxidant protection (52). Interestingly, we have observed that the Leishmania line overexpressing ABCI4 has a better survival inside mouse peritoneal macrophages than the other parasite lines, as determined by the significantly higher replication at 72 h postinfection.…”

Section: Discussionmentioning

confidence: 78%

A New ABC Half-Transporter in Leishmania major Is Involved in Resistance to Antimony

Manzano

García-Hernández

Castanys

et al. 2013

Antimicrob Agents Chemother

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The characterization of ABCI4, a new intracellular ATP-binding cassette (ABC) half-transporter in Leishmania major, is described. We show that ABCI4 is involved in heavy metal export, thereby conferring resistance to Pentostam, to Sb(III), and to As(III) and Cd(II). Parasites overexpressing ABCI4 showed a lower mitochondrial toxic effect of antimony by decreasing reactive oxygen species production and maintained higher values of both the mitochondrial electrochemical potential and total ATP levels with respect to controls. The ABCI4 half-transporter forms homodimers as determined by a coimmunoprecipitation assay. A combination of subcellular localization studies under a confocal microscope and a surface biotinylation assay using parasites expressing green fluorescent protein-and FLAG-tagged ABCI4 suggests that the transporter presents a dual localization in both mitochondria and the plasma membrane. Parasites overexpressing ABCI4 present an increased replication in mouse peritoneal macrophages. We have determined that porphyrins are substrates for ABCI4. Consequently, the overexpression of ABCI4 confers resistance to some toxic porphyrins, such as zinc-protoporphyrin, due to the lower accumulation resulting from a significant efflux, as determined using the fluorescent zinc-mesoporphyrin, a validated heme analog. In addition, ABCI4 has a significant ability to efflux thiol after Sb(III) incubation, thus meaning that ABCI4 could be considered to be a potential thiol-X-pump that is able to recognize metal-conjugated thiols. In summary, we have shown that this new ABC transporter is involved in drug sensitivity to antimony and other compounds by efflux as conjugated thiol complexes.

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“…The production of nitric oxide by macrophages is one of the main microbicidal mechanisms involved in the killing of intracellular forms of these parasites (54). Thus, we evaluated NO production in murine macrophages incubated with resveratrol and AMB.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Is Active against Leishmania amazonensis: In Vitro Effect of Its Association with Amphotericin B

Ferreira

Soares

Nascimento

et al. 2014

Antimicrob Agents Chemother

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Resveratrol is a polyphenol found in black grapes and red wine and has many biological activities. In this study, we evaluated the effect of resveratrol alone and in association with amphotericin B (AMB) against Leishmania amazonensis. Our results demonstrate that resveratrol possesses both antipromastigote and antiamastigote effects, with 50% inhibitory concentrations (IC 50 s) of 27 and 42 M, respectively. The association of resveratrol with AMB showed synergy for L. amazonensis amastigotes, as demonstrated by the mean sums of fractional inhibitory index concentration (mean ⌺FIC) of 0.483, although for promastigotes, this association was indifferent. Treatment with resveratrol increased the percentage of promastigotes in the sub-G 0 /G 1 phase of the cell cycle, reduced the mitochondrial potential, and showed an elevated choline peak and CH 2 -to-CH 3 ratio in the nuclear magnetic resonance (NMR) spectroscopy analysis; all these features indicate parasite death. Resveratrol also decreased the activity of the enzyme arginase in uninfected and infected macrophages with and without stimulation with interleukin-4 (IL-4), also implicating arginase inhibition in parasite death. The anti-Leishmania effect of resveratrol and its potential synergistic association with AMB indicate that these compounds should be subjected to further studies of drug association therapy in vivo.

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Leishmania–macrophage interactions: Insights into the redox biology

Cited by 204 publications

References 203 publications

Phosphorylation of Translation Initiation Factor 2-Alpha in Leishmania donovani under Stress Is Necessary for Parasite Survival

Phosphorylation of Translation Initiation Factor 2-Alpha in Leishmania donovani under Stress Is Necessary for Parasite Survival

A New ABC Half-Transporter in Leishmania major Is Involved in Resistance to Antimony

Resveratrol Is Active against Leishmania amazonensis: In Vitro Effect of Its Association with Amphotericin B

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