<i>Leishmania</i> hijacking of the macrophage intracellular compartments

Moal, Vanessa Liévin-Le; Loiseau, Philippe M.

doi:10.1111/febs.13601

Cited by 45 publications

(27 citation statements)

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“…Similarly to other exosome markers, such as the heat shock proteins HSP70 and HSP90 (43,61) and the L. major virulence factor P46 (65,66), HA 3 -LmPRL-1 was identified inside the cytoplasm of infected macrophages and colocalized with the late phagosomal marker LAMP-1 on the surfaces of PV, where it is ideally positioned to manipulate host cell signaling pathways in favor of the parasite (67). It is possible that LmPRL-1 directly modulates the phosphorylation status of host signaling molecules and thereby also synergizes with other secreted virulence factors of L. major.…”

Section: Discussionmentioning

confidence: 98%

Characterization of the Protein Tyrosine Phosphatase LmPRL-1 Secreted by Leishmania major via the Exosome Pathway

et al. 2017

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Similar to other intracellular pathogens, Leishmania parasites are known to evade the antimicrobial effector functions of host immune cells. To date, however, only a few virulence factors have been described for Leishmania major, one of the causative agents of cutaneous leishmaniasis. Here, we have characterized the expression and function of an L. major phosphatase, which we termed LmPRL-1. This enzyme shows a strong structural similarity to the human phosphatases of regenerating liver (PRL-1, -2, and -3) that regulate the proliferation, differentiation, and motility of cells. The biochemical characterization of the L. major phosphatase revealed that the enzyme is redox sensitive. When analyzing the subcellular localization of LmPRL-1 in promastigotes, amastigotes, and infected macrophages, we found that the phosphatase was predominantly expressed and secreted by promastigotes via the exosome route. Finally, we observed that ectopic expression of LmPRL-1 in L. major led to an increased number of parasites in macrophages. From these data, we conclude that the L. major phosphatase LmPRL-1 contributes to the intracellular survival of the parasites in macrophages.KEYWORDS Leishmania, exosome, macrophage, tyrosine phosphatase L eishmaniasis is an infectious disease prevalent worldwide that is caused by kinetoplastid protozoan parasites belonging to the genus Leishmania (1). In nature, this heteroxenous parasite is transmitted by the bites of sand flies. Following the inoculation of flagellated promastigotes into the dermis of the host, the parasites are rapidly endocytosed by phagocytic cells, in which they differentiate into amastigotes, multiply, and reach inner compartments and organs, such as draining lymph nodes, spleen, liver, and bone marrow. The life cycle of the parasite is completed after ingestion of amastigote-infected cells by sand flies during their blood meal. In the digestive tract of their vector, parasites transform back into extracellular promastigotes that develop into infectious metacyclics (2). Depending on the status of the host immune system and the Leishmania species, the infection of mammals leads either to mostly self-healing skin lesions (cutaneous leishmaniasis [CL]) or to a systemic disease, termed visceral leishmaniasis (VL) or kala-azar, that is lethal if untreated (3-5).To survive in their hosts, Leishmania parasites need to quickly adapt their growth, metabolism, and mechanisms of protection to their new environment. Interestingly, only a few genes are differentially expressed during this adaptive process, suggesting an important role for the regulation of protein translation (6). Leishmania speciesspecific gene diversity also participates in the adaptation of the parasite to its organ-

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Section: Discussionmentioning

confidence: 98%

Characterization of the Protein Tyrosine Phosphatase LmPRL-1 Secreted by Leishmania major via the Exosome Pathway

et al. 2017

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“…It has been shown that host cell receptors (for example Complement receptors and Fcγ) influence L. donovani internalization and this interaction is partially dependent on the presence of promastigote flagella [49]. It is also documented that host cell membrane microdomains influence internalization of the parasite [5,7,50] . In order to hijack the cellular defense machinery L. donovani interacts with components of endoplasmic reticulum and the trans-Golgi network (TGN) [7,51].…”

Section: Intracellular Life Of L Donovani: the Role Of Wnt5a Signalimentioning

confidence: 99%

“…L. donovani invades mostly host macrophages and also dendritic cells and neutrophils, hijacking the cellular machinery for its survival through adopting various strategies to evade immune response [5]. One of the strategies employed by the parasite is to inhibit phagolysosomal maturation by altering host cell lysosomal integrity [6].…”

Section: Introductionmentioning

confidence: 99%

Wnt5A Signaling AntagonizesLeishmania donovaniInfection

Chakraborty¹,

Maity²,

Sen³

2020

Vector-Borne Diseases - Recent Developments in Epidemiology and Control

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Infection by the parasite Leishmania donovani causes Visceral Leishmaniasis, a deadly disease if not properly treated. L. donovani captures the immune defense potential of host macrophages. It disrupts immune homeostasis at least partly by inducing expression of anti-inflammatory cytokines and altering the cellular cytoskeletal framework, thereby creating a niche for its own survival. While inhibition of macrophage Wnt5A signaling promotes infection by the parasite, activation of Wnt5A signaling significantly dampens infection. Experimental evidence suggests that the antagonistic effect of Wnt5A signaling on parasite infection in macrophages may be on account of its influence on the actin cytoskeleton. Importantly, the inhibitory effect of Wnt5A on infection is sustained independent of drug sensitivity and resistance. Keeping in mind that drugs used to treat Visceral Leishmaniasis are quite toxic and the parasite develops drug resistance, revamping host Wnt5A signaling may be useful for eliminating infection independent of drug sensitivity or resistance.

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“…This Minireview series on Intracellular Pathogens describes the intra-macrophagic escape and survival mechanisms developed by very different intracellular pathogens: the bacteria of the Chlamydiales order [1], the parasite Leishmania [2] and the fungus Histoplasma capsulatum [3]. All three pathogens are internalized into macrophages by receptor-mediated endocytosis, involving specific receptors for each microorganism [4][5][6].…”

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confidence: 99%

“…The Minireviews in this series discuss the recent advances in understanding the complex dance between microorganism and macrophage [1][2][3]. Importantly, they highlight the common strategies employed by each pathogen to circumvent host defense, and as such will be useful in considering future therapeutic angles.…”

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confidence: 99%

Intracellular pathogens convert macrophages from death traps into hospitable homes

2016

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Infectious microorganisms must find ways to escape or counteract the immune defenses of the host during the course of infection. The innate and adaptive immune functions of a healthy host represent serious threats for the invader and most microorganisms cannot survive in this hostile environment. One strategy to escape that is shared by many pathogenic bacteria, parasites and fungi is to hide in cells and turn them into welcoming refuges where they can multiply. In this context, the macrophage is a key cell to infect.Macrophages are at the crossroads of immune defenses, as they participate at the onset of the innate and adaptive immune responses. Innate immunity is a fast response triggered by the early detection of pathogen molecules, which involves the phagocytosis of the microorganisms for their destruction in the phagosome, and the secretion of cell factors that attack microorganisms outside and inside the macrophage and factors to attract other immune cells to the site of infection. Among these defense factors are toxic effector molecules (such as reactive oxygen species and nitric oxides, proteases, nucleases, lipases and others) and pro-inflammation chemokines and cytokines to attract or activate monocytes, neutrophils, lymphocytes and other immune cells. Together with other monocyte cells such as the dendritic cells, the macrophage presents protein peptides from the pathogen to helper T lymphocytes to stimulate the ones capable of responding to the infection by activating the B lymphocytes displaying the proper anti-pathogen antibodies. The macrophage can also cooperate with cytotoxic T lymphocytes for the destruction of cells infected with pathogens.This Minireview series on Intracellular Pathogens describes the intra-macrophagic escape and survival mechanisms developed by very different intracellular pathogens: the bacteria of the Chlamydiales order [1], the parasite Leishmania [2] and the fungus Histoplasma capsulatum [3]. All three pathogens are internalized into macrophages by receptor-mediated endocytosis, involving specific receptors for each microorganism [4][5][6]. They differentiate into a novel stage with very different biological properties. Chlamydiales change from infectious non-replicating elementary bodies to nonJulien Barbier is principal investigator at CEA, a biochemist and cell biologist. He studied animal and bacterial toxins for 15 years. He performed the high-throughput screen that led to the identification of inhibitors of intracellular retrograde transport. He is currently studying the mechanisms of transport inhibition, identifying inhibitors' cellular targets and screening for improved inhibitors.Jean-Christophe Cintrat is a senior scientist in bioorganic chemistry at CEA. He is an expert in drug discovery, molecule screening, medicinal chemistry and molecule labeling. He is currently working on the development of inhibitors of intracellular trafficking as broad-spectrum drugs against intracellular pathogens, and screening for novel anti-pathogen molecules.Daniel Gillet is a Re...

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Leishmania hijacking of the macrophage intracellular compartments

Cited by 45 publications

References 121 publications

Characterization of the Protein Tyrosine Phosphatase LmPRL-1 Secreted by Leishmania major via the Exosome Pathway

Characterization of the Protein Tyrosine Phosphatase LmPRL-1 Secreted by Leishmania major via the Exosome Pathway

Wnt5A Signaling AntagonizesLeishmania donovaniInfection

Intracellular pathogens convert macrophages from death traps into hospitable homes

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