Leishmania tropica: Pathogenicity and in vitro macrophage function in strains of inbred mice

Behin, Reza; Mauël, Jacques; Sordat, Bernard

doi:10.1016/0014-4894(79)90057-2

Cited by 140 publications

(72 citation statements)

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“…mexicana (WHO reference strain MYNC/BZ/62/M379) and L. major [Liverpool reference strain LV39 (MRHO/SU/59/P)] promastigotes were isolated and propagated as published elsewhere [12,13]. Promastigotes of both species were used to infect human monocytic cell lines when in the stationary phase of growth.…”

Section: Methodsmentioning

confidence: 99%

Human monocytic U937 cells transfected with human hepatic inducible nitric oxide synthase exhibit leishmanicidal activity

Bertholet

Mauël

2000

Journal of Leukocyte Biology

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Section: Methodsmentioning

confidence: 99%

Human monocytic U937 cells transfected with human hepatic inducible nitric oxide synthase exhibit leishmanicidal activity

Bertholet

Mauël

2000

Journal of Leukocyte Biology

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“…Leishmania-L. major promastigotes (strain MRHO/SU/59/P designated as LV39) were grown at 26°C in Dulbecco's minimal essential medium on blood agar (27). Stationary phase promastigotes were washed three times in phosphate-buffered saline and resuspended in phosphate-buffered saline at 10 6 /l for experiments measuring the effect of live parasites on recombinant MRP.…”

Section: Methodsmentioning

confidence: 99%

MARCKS-related Protein (MRP) Is a Substrate for the Leishmania major Surface Protease Leishmanolysin (gp63)

Corradin¹,

Ransijn²,

Corradin³

et al. 1999

Journal of Biological Chemistry

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Myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS-related protein (MRP; MacMARCKS) are protein kinase C substrates in diverse cell types. Activation of murine macrophages by cytokines increases MRP expression, but infection with Leishmania promastigotes during activation results in MRP depletion. We therefore examined the effect of Leishmania major LV39 on recombinant MRP. Both live promastigotes and a soluble fraction of LV39 lysates degraded MRP to yield lower molecular weight fragments. Degradation was independent of MRP myristoylation and was inhibited by protein kinase C-dependent phosphorylation of MRP. MRP was similarly degraded by purified leishmanolysin (gp63), a Leishmania surface metalloprotease. Degradation was evident at low enzyme/substrate ratios, over a broad pH range, and was inhibited by 1,10-phenanthroline and by a hydroxamate dipeptide inhibitor of leishmanolysin. Using mass spectrometric analysis, cleavage was shown to occur within the effector domain of MRP between Ser 92 and Phe 93, in accordance with the substrate specificity of leishmanolysin. Moreover, an MRP construct in which the effector domain had been deleted was resistant to cleavage. Thus, Leishmania infection may result in leishmanolysin-dependent hydrolysis of MRP, a major protein kinase C substrate in macrophages.Myristoylated alanine-rich C kinase substrate (MARCKS) 1 and MARCKS-related protein (MRP), also known as Mac-MARCKS, are members of a highly acidic myristoylated family of protein kinase C (PKC) substrates (1, 2). The primary structures of MARCKS and MRP exhibit significant homology, including a highly basic stretch of amino acid residues known as the effector domain (also as the phosphorylation site domain), which contains the serine residues subject to PKC-dependent phosphorylation as well as binding sites for calmodulin and actin. Whereas MARCKS is widely distributed in diverse cell types, MRP is present primarily in brain and reproductive tissue (3, 4) as well as in macrophages, where it was first characterized (5). The biologic functions of MARCKS proteins are unknown. Due to their high effector domain homology, it is also possible that MRP and MARCKS play overlapping roles in some cells. In macrophages, both proteins colocalize in the cytosol in association with components of the actin cytoskeleton (6 -9) and consequently are thought to participate in major cellular responses such as phagocytosis, motility, and membrane trafficking.The expression of MARCKS proteins appears to be highly regulated, and in vitro studies have demonstrated up-or downregulation of MARCKS at both the transcriptional and posttranscriptional levels (5, 10, 11). One mechanism of post-transcriptional regulation involves proteolytic degradation. Spizz and Blackshear (12) recently identified cathepsin B as a cellular MARCKS-cleaving enzyme in fibroblasts. They suggested that cleavage might occur within lysosomes as a result of specific lysosomal targeting sequences identified within the MARCKS primary sequence. At least one c...

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“…Thus mice are completely resistant to infection by L. enriettii; this correlates with the observation that activated macrophages from this host species readily destroy the parasite in vitro (Benin, Mauel, Biroum-Noerjasin & Rowe, 1975;Mauel, Buchmiiller & Behin, 1978). A similar parallel can be found in the infection of mice by L. tropica; genetically determined variations can be detected between mice from different inbred strains as regards their susceptibility to infection by this parasite (Preston & Dumonde, 1976;Behin, Mauel & Sordat, 1979;Handman, Ceredig & Mitchell, 1979). Whereas 'susceptible' animals tend to carry infection for their lifetime,' resistant' ones do produce a skin infection at first, then succeed in eliminating the pathogen, presumably through an immune response leading to macrophage activation.…”

Section: The Fate Of Intbac Ellul Ab Microorganisms As Determined By mentioning

confidence: 78%

“…Whereas 'susceptible' animals tend to carry infection for their lifetime,' resistant' ones do produce a skin infection at first, then succeed in eliminating the pathogen, presumably through an immune response leading to macrophage activation. In vitro studies have shown that activated macrophages from ' resistant' hosts are more efficient at killing the parasite than are activated macrophages from susceptible ones (Behin et al 1979). It is important to note, however, that the deficiency observed in activated 'susceptible' macrophages is only partial: indeed, under culture conditions favouring maximal activation, susceptible macrophages (with respect to L. tropica infection) are able to eliminate the parasite completely.…”

Section: The Fate Of Intbac Ellul Ab Microorganisms As Determined By mentioning

confidence: 99%

Mechanisms of survival of protozoan parasites in mononuclear phagocytes

Mauël¹

1984

Parasitology

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SUMMARYThe understanding of the mechanisms whereby intracellular parasites counteract the microbicidal processes of macrophages has progressed considerably in recent years. Various factors contribute to intracellular parasite destruction; from a biochemical standpoint, particularly important is the oxidative burst triggered by phagocytosis and by macrophage 'activation', that leads to the generation of toxic metabolites of oxygen. At the ultrastructural level, fusion of the parasitophorous vacuole with surrounding lysosomes appears to be a pre-requisite for the final digestion and elimination of the infecting microorganisms. The counter-measures evolved by microorganisms to escape intracellular destruction are best illustrated by studies in vitro on the interaction of parasites of the Leishmania, Toxoplasma and Trypanosoma spp. with mononuclear phagocytes. Some microbes are able to inhibit the fusion of phagosomes with lysosomes, thus avoiding the potentially harmful action of lysosomal hydrolases. Other microorganisms are able to resist the effects of such enzymes, perhaps by secreting inhibitory substances. Others still avoid lysosomes by leaving the phagocytic vacuole, to reach the cytoplasmic matrix where their development is unhindered. Particularly critical is the capacity of certain parasites to subvert the lethal effects of the oxidative burst. This can be achieved either by failing to evoke this metabolic response, or by producing scavengers that can detoxify harmful oxygen metabolites. Intracellular death or survival will thus depend on a delicate balance between the potency of macrophage cidal mechanisms, and the efficacy of the protective measures evolved by the infecting agents.

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Leishmania tropica: Pathogenicity and in vitro macrophage function in strains of inbred mice

Cited by 140 publications

References 2 publications

Human monocytic U937 cells transfected with human hepatic inducible nitric oxide synthase exhibit leishmanicidal activity

Human monocytic U937 cells transfected with human hepatic inducible nitric oxide synthase exhibit leishmanicidal activity

MARCKS-related Protein (MRP) Is a Substrate for the Leishmania major Surface Protease Leishmanolysin (gp63)

Mechanisms of survival of protozoan parasites in mononuclear phagocytes

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