Leishmania virulence factors: focus on the metalloprotease GP63

Olivier, Martin; Atayde, Vanessa D.; Isnard, Amandine; Hassani, Kasra; Shio, Marina Tiemi

doi:10.1016/j.micinf.2012.05.014

Cited by 175 publications

(185 citation statements)

References 85 publications

(105 reference statements)

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“…Interestingly, several Leishmania surfaceexpressed and secreted molecules like glycosylinositol-phospholipids (GIPLs), lipophosphoglycan (LPG), cysteine-protease and metalloprotease gp63 (Ldgp63) have been shown to inactivate macrophage functions and thereby parasite is able to counter the microbicidal activity of macrophages (3,4). Amongst these, Ldgp63 secreted by Leishmania has been shown to be the major virulence factor required for entry and intracellular survival of the parasites in macrophages (5)(6)(7)(8). For instances, Ldgp63 cleaves complement factor C3b to iC3b to prevent not only the complement mediated lysis of the parasite but also enables the uptake of parasites by complement receptors on macrophages (9,10).…”

Section: Introductionmentioning

confidence: 99%

GTPase Sar1 regulates the trafficking and secretion of the virulence factor gp63 in Leishmania

Parashar

Mukhopadhyay

2017

Journal of Biological Chemistry

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Section: Introductionmentioning

confidence: 99%

GTPase Sar1 regulates the trafficking and secretion of the virulence factor gp63 in Leishmania

Parashar

Mukhopadhyay

2017

Journal of Biological Chemistry

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“…A salient feature of Leishmania parasites is their capacity to alter phagocyte biology through pathogenicity factors such as lipophosphoglycan (LPG) and the zinc metalloprotease GP63, both of which are predominant at the promastigote stage of the parasite (8,(10)(11)(12). GP63 cleaves proteins involved in the regulation of phagocyte functions (13), leading to altered cell signaling, to subversion of transcription and translation (14)(15)(16)(17), Ag cross-presentation (18), lipid metabolism (19,20), and likely to other unknown effects.…”

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confidence: 99%

Leishmania Promastigotes Induce Cytokine Secretion in Macrophages through the Degradation of Synaptotagmin XI

Duque

Fukuda

Turco

et al. 2014

The Journal of Immunology

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Synaptotagmins (Syts) are type-I membrane proteins that regulate vesicle docking and fusion in processes such as exocytosis and phagocytosis. We recently discovered that Syt XI is a recycling endosome- and lysosome-associated protein that negatively regulates the secretion of TNF and IL-6. In this study, we show that Syt XI is directly degraded by the zinc metalloprotease GP63 and excluded from Leishmania parasitophorous vacuoles by the promastigotes surface glycolipid lipophosphoglycan. Infected macrophages were found to release TNF and IL-6 in a GP63-dependent manner. To demonstrate that cytokine release was dependent on GP63-mediated degradation of Syt XI, small interfering RNA-mediated knockdown of Syt XI before infection revealed that the effects of small interfering RNA knockdown and GP63 degradation were not cumulative. In mice, i.p. injection of GP63-expressing parasites led to an increase in TNF and IL-6 secretion and to an augmented influx of neutrophils and inflammatory monocytes to the inoculation site. Both of these cell types have been shown to be infection targets and aid in the establishment of infection. In sum, our data revealed that GP63 induces proinflammatory cytokine release and increases infiltration of inflammatory phagocytes. This study provides new insight on how Leishmania exploits the immune response to establish infection.

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“…These exosomes are cargo vesicles produced by promastigotes and amastigotes and used as a main secretory pathway (15,56). They are loaded with cytoplasmic and membrane proteins of the parasite, including known virulence factors, such as the surface protease leishmanolysin (Gp63) or EF-1␣ (23,24,61). Moreover, exosomes are released within the sand fly gut and are inoculated into the host along with the parasites (62).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, another well-studied immunomodulatory molecule of Leishmania is its promastigote surface molecule lipophosphoglycan (LPG) (19,20), which delays the fusion of the phagosome with late endosomes or lysosomes in macrophages (21,22). In addition, parasites secrete virulence factors, such as the zinc metalloprotease Gp63 (also known as leishmanolysin) or the elongation factor EF-1␣, to inhibit the production of leishmanicidal nitric oxide or of proinflammatory cytokines by macrophages (15,23,24). These two parasite-derived factors lead to the rapid activation of src homology 2 domain-containing tyrosine phosphatase 1 (SHP-1) and other host phosphatases (25,26), the modulation of protein kinase C (PKC) activities (27,28), the inhibition of mitogen-activated protein kinase (MAPK) (29,30), and the disruption of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway after Leishmania infection (14,25,31).…”

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confidence: 99%

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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Leishmania virulence factors: focus on the metalloprotease GP63

Cited by 175 publications

References 85 publications

GTPase Sar1 regulates the trafficking and secretion of the virulence factor gp63 in Leishmania

GTPase Sar1 regulates the trafficking and secretion of the virulence factor gp63 in Leishmania

Leishmania Promastigotes Induce Cytokine Secretion in Macrophages through the Degradation of Synaptotagmin XI

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

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