Leishmania survival in the macrophage: where the ends justify the means

Duque, Guillermo Arango; Descoteaux, Albert

doi:10.1016/j.mib.2015.04.007

Cited by 92 publications

(66 citation statements)

References 67 publications

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“…Leishmania promastigotes preferentially infect macrophages in their mammalian hosts. The infection leads to subversion/modulation of the host’s innate immune response and cellular metabolic pathways, thereby allowing parasite survival and replication [1,2]. Notably, parasitized cells become resistant to apoptosis [3–5], therefore the death of infected macrophages is delayed.…”

Section: Introductionmentioning

confidence: 99%

Leishmania infantum Induces Mild Unfolded Protein Response in Infected Macrophages

et al. 2016

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The Leishmaniases are a group of parasitic diseases caused by protozoa of the Leishmania genus affecting both humans and other vertebrates. Leishmania is an intracellular pathogen able to confer resistance to apoptosis in the early phase of macrophages infection by activation of host PI3K/Akt pathway and inhibition of caspase-3 activation. Intracellular pathogens hijack organelles such as ER to facilitate survival and replication, thus eliciting ER stress and activating/modulating the unfolded protein response (UPR) in the host cell. The UPR is aimed to mitigate ER stress, thereby promoting cell survival. However, prolonged ER stress will activate the apoptotic pathway. The aim of this study was to investigate the ER stress response in Leishmania-infected macrophages to gain insights about the mechanisms underlying the apoptosis resistance in parasitized cells. Macrophages differentiated from human monocytic cell lines (U937 and THP-1) and murine primary macrophages were infected with Leishmania infantum MHOM/TN/80/IPT1 (WHO international reference strain). Several ER stress/autophagy expression markers, as well as cell survival/apoptosis markers (phospho-Akt and cleaved caspase-3) were evaluated by qPCR and/or by western blotting. As ER stress positive control, cells were treated with tunicamycin or dithiothreitol (DTT). The gene expression analyses showed a mild but significant induction of the ER stress/autophagy markers. The western blot analyses revealed that the Leishmania infection induced Akt phosphorylation and significantly inhibited the induction of caspase-3 cleavage, eIF2α phosphorylation and DDIT3/CHOP expression in tunicamycin and DTT treated cells. The mild but significant increase in ER stress expression markers and the delay/attenuation of the effects of ER stress inducers in infected cells support the hypothesis that L. infantum could promote survival of host cells by inducing a mild ER stress response. The host ER stress response could be not only a common pathogenic mechanism among Leishmania species but also a target for development of new drugs.

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Section: Introductionmentioning

confidence: 99%

Leishmania infantum Induces Mild Unfolded Protein Response in Infected Macrophages

et al. 2016

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“…2C). Notably, genetic deletion of GP63, another potent leishmanial virulence factor (16,37), did not prevent CXCL16 induction by L. major promastigotes. Moreover, New World strains L. infantum Ba262 (Brazil) and L. mexicana M379 (Belize) were also able to enhance CXCL16 expression in BMDM ( Fig.…”

Section: Resultsmentioning

confidence: 95%

Leishmania donovani Lipophosphoglycan Increases Macrophage-Dependent Chemotaxis of CXCR6-Expressing Cells via CXCL16 Induction

et al. 2019

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CXCL16 is a multifunctional chemokine that is highly expressed by macrophages and other immune cells in response to bacterial and viral pathogens; however, little is known regarding the role of CXCL16 during parasitic infections. The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis. Even though chemokine production is a host defense mechanism during infection, subversion of the host chemokine system constitutes a survival strategy adopted by the parasite. Here, we report that L. donovani promastigotes upregulate CXCL16 synthesis and secretion by bone marrow-derived macrophages (BMDM). In contrast to wild-type parasites, a strain deficient in the virulence factor lipophosphoglycan (LPG) failed to induce CXCL16 production. Consistent with this, cell treatment with purified L. donovani LPG augmented CXCL16 expression and secretion. Notably, the ability of BMDM to promote migration of cells expressing CXCR6, the cognate receptor of CXCL16, was augmented upon L. donovani infection in a CXCL16-and LPG-dependent manner. Mechanistically, CXCL16 induction by L. donovani required the activity of AKT and the mechanistic target of rapamycin (mTOR) but was independent of Toll-like receptor signaling. Collectively, these data provide evidence that CXCL16 is part of the inflammatory response elicited by L. donovani LPG in vitro. Further investigation using CXCL16 knockout mice is required to determine whether this chemokine contributes to the pathogenesis of visceral leishmaniasis and to elucidate the underlying molecular mechanisms.

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“…Following transmission of the insect-stage promastigote form of the parasite to vertebrate hosts by blood-feeding infected sand flies, the parasite develops into the amastigote form inside the fully acidified phagolysosomes of host macrophages (Antoine et al, 1998;Zilberstein and Shapira, 1994). Intracellular amastigotes manipulate host cell signaling, immune functions, and metabolism to establish permissive conditions for long-term chronic infection (Arango Duque and Descoteaux, 2015;Giraud et al, 2012;Lecoeur et al, 2010;Lecoeur et al, 2013;McConville et al, 2015;Olivier et al, 2005; Osorio y Fortea et al, 2009;Osorio y Fortea et al, 2007). In recent years, the impact of intracellular Leishmania infection on the NF-B-mediated and inflammasome-dependent proinflammatory response has attracted important attention.…”

Section: Introductionmentioning

confidence: 99%

Leishmaniatargets the macrophage epigenome and dampens the NF-κB/NLRP3-mediated inflammatory response

Lecœur

Prina

Rosazza

et al. 2019

Preprint

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Aberrant macrophage activation during intracellular infection generates importantimmunopathologies that can cause severe human morbidity. A better understanding of microbial immune subversion strategies and macrophage phenotypic and functional responses is a prerequisite for the design of novel, host-directed intervention strategies. Here, we uncover a fine-tuned transcriptional response induced in primary macrophages infected by the human parasite Leishmania amazonensis that prevents NF-B and NLRP3 inflammasome activation.This unusual subversion is characterized by respectively suppression and induction of activating and de-activating components of the NF-B and NLRP3 pathways. This dichotomic modulation was associated with histone H3 hypoacetylation at promoters of NF-B-related, pro-inflammatory genes. Our results reveal a novel Leishmania immune subversion strategy targeting host cell epigenetic regulation to modulate the macrophage phenotype. Modulation of the macrophage epigenetic landscape establishes conditions beneficial for intracellular parasite survival, and opens interesting new venues for host-directed, anti-microbial drug discovery.

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Leishmania survival in the macrophage: where the ends justify the means

Cited by 92 publications

References 67 publications

Leishmania infantum Induces Mild Unfolded Protein Response in Infected Macrophages

Leishmania infantum Induces Mild Unfolded Protein Response in Infected Macrophages

Leishmania donovani Lipophosphoglycan Increases Macrophage-Dependent Chemotaxis of CXCR6-Expressing Cells via CXCL16 Induction

Leishmaniatargets the macrophage epigenome and dampens the NF-κB/NLRP3-mediated inflammatory response

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