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PubMed1999

Proteophosphoglycans of Leishmania mexicana. Molecular cloning and characterization of the Leishmania mexicana ppg2 gene encoding the proteophosphoglycans aPPG and pPPG2 that are secreted by amastigotes and promastigotes.

Intracellular amastigotes of the pathogenic protozoon Leishmania mexicana secrete an extensively phosphoglycosylated proteophosphoglycan (aPPG) into the phagolysosome of mammalian host macrophages, that appears to fulfil important functions for the parasites. Promastigotes (the sandfly vector forms) of the same species secrete a proteophosphoglycan with identical protein backbone but exhibiting stage-specific phosphoglycosylation patterns [Klein, Göpfert, Goehring, Stierhof and Ilg (1999) Biochem. J. 344, 775-786]. In this study we report the cloning of the novel repeat-containing proteophosphoglycan gene ppg2 by antibody screening of a Leishmania mexicana amastigote cDNA expression library. ppg2 is equally expressed in promastigotes and amastigotes at the mRNA level. Targeted gene replacement of both alleles of the single copy gene ppg2 results in the loss of pPPG2 expression in promastigotes. Antisera against Escherichia coli-expressed ppg2 recognize the deglycosylated forms of aPPG as well as pPPG2. These results confirm that ppg2 encodes the protein backbones of aPPG and pPPG2. An unusual finding is that ppg2 exhibits two stable allelic forms, ppg2a and ppg2b. Their main difference lies in the number of central 72 bp DNA repeats (7 versus 8). ppg2a and ppg2b encode polypeptide chains of 574 and 598 amino acids, respectively, that show no homology to known proteins. The novel 24 amino acid Ser-rich peptide repeats encoded by the 72 bp DNA repeats are targets for Ser phosphoglycosylation in Leishmania mexicana.

Alleles↗
PubMed2002

Immunochemotherapy for cutaneous leishmaniasis: a controlled trial using killed Leishmania (Leishmania) amazonensis vaccine plus antimonial.

BACKGROUND: Leishmaniasis is endemic in 88 countries in the world, and 350 million individuals are at risk of acquiring the disease. Treatment for American cutaneous leishmaniasis (ACL) is long, expensive, and associated with important side-effects. METHODS: In this double-blind, placebo-controlled study, we treated 102 patients with ACL using either a combination of a single-strain Leishmania amazonensis killed promastigote vaccine plus a half dose of meglumine antimoniate, or placebo plus the same half dose regimen of meglumine antimoniate, in 10-day series followed by 10-day intervals. RESULTS: Of the 47 patients in the experimental arm, 47 (100%) were cured after four series of treatment, compared to four of 49 (8.2%) in the control group (P < 0.0001). Six patients were lost to follow-up. CONCLUSIONS: The combination of a single-strain Leishmania (Leishmania) amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL.

Adolescent↗
PubMed1993

Successful transient introduction of Leishmania RNA virus into a virally infected and an uninfected strain of Leishmania.

Viruses of Leishmania have recently been identified and characterized. These viruses are consistently double-stranded RNA viruses of approximately 5 kb. To date, they have not been reported to exist outside their protozoan host, nor have they been shown to be infectious. We report here the ability to transiently transfer these viruses to two strains of Leishmania, one previously infected and one that did not previously carry a virus. A PCR-based assay was used to detect viral negative-stranded RNA. Input RNA was ruled out as the source of template because a replication-incompetent (UV inactivated) virus was not detectable after transfer into Leishmania.

Animals↗
PubMed1995

Identification of Leishmania species by a specific DNA probe that is conserved only in the maxicircle DNA of human-infective Leishmania parasites.

An A + T-rich repeated DNA sequence cloned from maxicircle DNA of Leishmania mexicana amazonensis was found to be conserved in the maxicircles of human-infective Leishmania species but totally absent from non-human-infective ones. Differences in the pattern of distribution of this repeated sequence in the maxicircles of each human-infective Leishmania species potentially allow the development of a sensitive probe to differentiate among these species.

Animals↗
PubMed1995

Phylogenetic analysis of Leishmania RNA virus and Leishmania suggests ancient virus-parasite association.

Some strains of the protozoan parasite Leishmania belonging to the new world species guyanensis and braziliensis are infected with persistent, single-segmented, non-enveloped dsRNA viruses termed LRV1. A single old world strain classified as L. major was recently found to harbor a similar virus, designated LRV2-1. The genomic nucleotide sequences of two LRV1 types (1-1 and 1-4) isolated from two L. guyanensis strains have been determined and found to be highly conserved. In contrast, LRV1-specific cDNA probes derived from the conserved genomic 5' region failed to recognize LRV2 RNA on Northern blots, suggesting a greater degree of divergence between LRV1 and LRV2 than among LRV1 types. This observation suggests a long-term association and coevolution of LRV within each parasite strain. We tested this concept by comparing nucleotide sequences of seven LRV types and PCR fingerprints of the parasite strains from which these viruses were derived. In support of the idea of virus-parasite co-evolution, we find that genetic distances between LRV types mirror the heterogeneity between parasite fingerprints and are clustered according to the geographical origin of the strains. In agreement with the postulated common origin of persistent dsRNA viruses of protozoa and fungi, we conclude that the infection of Leishmania with LRV pre-dates the divergence of Leishmania into different lineages.

Amino Acid Sequence↗
PubMed1994

Dichotomy of the human T cell response to Leishmania antigens. I. Th1-like response to Leishmania major promastigote antigens in individuals recovered from cutaneous leishmaniasis.

The T cell response to antigens from Leishmania major promastigotes was investigated in peripheral blood mononuclear cells from Sudanese individuals with a history of cutaneous leishmaniasis (CL), Sudanese individuals with positive DTH reaction in the leishmanin skin test but with no history of skin lesions, and in Danes without known exposure to Leishmania parasites. Proliferation and production of interferon-gamma (IFN-gamma) and IL-4 in antigen-stimulated cultures was measured. Lymphocytes from individuals with a history of CL proliferated vigorously and produced IFN-gamma after stimulation with either a crude preparation of L. major antigens or the major surface protease gp63. These cultures produced no or only little IL-4. Also cells from leishmanin skin test-positive donors with no history of CL produced IFN-gamma and no IL-4 in response to L. major antigens. Cells from the unexposed Danes were not activated by gp63. The cells from Danish donors produced either IFN-gamma or IL-4, but not both cytokines after incubation with the crude preparation of L. major antigens. The data show that the T cell response to Leishmania antigens in humans who have had uncomplicated CL or subclinical L. major infection is an IFN-gamma-producing Th1-like response.

Animals↗
PubMed2005

Interleukin-2-activated natural killer cells may have a direct role in the control of Leishmania (Leishmania) amazonensis promastigote and macrophage infection.

To study the role of Natural Killer (NK) cells in Leishmania infection, peritoneal macrophages from BALB/c mice were infected with Leishmania (Leishmania) amazonensis promastigotes and incubated with interleukin-2 (IL-2)-activated NK (A-NK) cells at different ratios of A-NK cells to infected macrophages (5:1, 1:1, 0.2:1). The A-NK cells were added either together with the parasites (0-h group) or 24 h later (24-h group). Morphological studies of the cultures revealed predominance of parasitic debris within macrophages that were in close contact with A-NK cells and the decrease in parasite recovery was directly proportional to the A-NK cell concentration used. Interferon-gamma (IFN-gamma) and IL-12 were detected in the supernatant at levels proportional to the A-NK cell concentration used. No significant difference was observed between the groups with respect to NO levels in the culture supernatant. When A-NK cells were added directly to the L. (L.) amazonensis promastigote cultures, the parasite recovery decreased proportional to the number of A-NK cells added. In vivo studies demonstrated smaller lesion sizes in animals inoculated with both parasites and A-NK cells compared with parasites alone. Histopathology of the skin lesions from animals receiving A-NK cells together with the parasites showed moderate parasitism and a nodular inflammatory infiltrate formed by mononuclear cells and a few vacuolized macrophages. In contrast, animals inoculated only with the parasites showed a highly parasitized dermis with infiltration of intensely vacuolized macrophages. These results demonstrate the role of A-NK cells in parasite lysis and in resistance of macrophages to L. (L.) amazonensis in the early phase of infection.

Animals↗
PubMed1977

Phosphofructokinase of Leishmania donovani and Leishmania braziliensis and its role in glycolysis.

It was shown in an investigation of the phosphofructokinases of Leishmania donovani and Leishmania braziliensis that both enzymes are similar to that of Crithidia fasciculata. Although the enzymes are allosteric with respect to their substrates and require AMP for activation, there is no influence by other heterotropic modifiers. The Mg2+-ATP chelate activates these enzymes in a first order process and they can be inhibited by free ATP. The inhibition is reversed by the activator, AMP, in a competitive manner. The requirement for the nucleotide in L. donovani can be eliminated by decreasing the pH. The data indicate that phosphofructokinase, a pivotal enzyme in glycolysis for most organisms, probably does not play an important role in glycolysis in Leishmania.

Adenosine Monophosphate↗
PubMedDate not supplied

Insulin-like growth factor-I induces phosphorylation in Leishmania (Leishmania) mexicana promastigotes and amastigotes.

Protein phosphorylation controls major steps of proliferation and differentiation in eukaryotic cells. However there are few studies done in protozoa particularly when being triggered by external stimuli. In this paper we have examined the tyrosine- and serine/threonine-phosphorylated proteins in both promastigote and amastigote-like forms of Leishmania (Leishmania) mexicana stimulated with insulin-like growth factor (IGF)-I. Stimulation with IGF-I induces major tyrosine phosphorylation of a 185-kDa protein in promastigotes and 60- and 40-kDa proteins in amastigotes. Analysis of total phosphorylation revealed additional sets of phosphorylated proteins: a 110-kDa protein band in promastigotes and two other proteins of 120 and 95 kDa in the amastigote-like forms. To further analyze the IGF-I-mediated response we compared it with the phosphorylation pattern obtained with a known inducer of protein kinase C, phorbol myristate acetate. This analysis showed overlapping phosphorylation of most of the proteins but mainly of the 185- and 110-kDa proteins in the promastigotes and the 95-, 60- and 40-kDa proteins in the amastigote-like forms. We thus conclude that there are phosphorylation-dependent pathways in Leishmania parasites induced by IGF-I that are stage-specific.

Animals↗
PubMed1993

Glycosphingolipid antigens of Leishmania (Leishmania) amazonensis amastigotes identified by use of a monoclonal antibody.

Monoclonal antibodies directed against Leishmania (Leishmania) amazonensis amastigotes were produced. One monoclonal antibody (1C3) selected by indirect immunofluorescence reacted with both amastigotes and promastigotes of L. (L.) amazonensis. Glycolipid extraction from L. (L.) amazonensis amastigotes and separation by high-performance thin-layer chromatography followed by immunoblotting demonstrated that 1C3 reacts with two glycosphingolipids which migrate chromatographically similarly to ceramide-N-acetylneuraminic acid (GM1) and ceramide-N-tetrose-di-acetylneuraminic acid (GD1a). The antibody did not react with glycosphingolipids from L. (L.) amazonensis promastigotes. Immunoprecipitation of 125I- and 35S-methionine-labeled promastigotes demonstrated that 1C3 recognizes gp63 from L. (L.) amazonensis promastigotes. Biosynthetic incorporation of labeled lipids by L. (L.) amazonensis amastigotes indicated that the glycosphingolipids reactive with 1C3 contain oleic acid in their structures. Surface labeling with galactose oxidase and sodium boro[3H]hydride indicated that galactose is present in 1C3-reactive antigens, strongly suggesting that these glycosphingolipids are localized on the surface of L. (L.) amazonensis amastigotes. Inhibition experiments of macrophage infection implicated the 1C3-reactive glycosphingolipids from L. (L.) amazonensis amastigotes in Leishmania invasion. The role of gp63 in promastigote-macrophage attachment was also demonstrated by inhibition experiments performed with 1C3, consistent with data from the literature.

Animals↗
PubMed1992

Canine leishmaniasis caused by Leishmania leishmania infantum in two Labrador retrievers.

Canine leishmaniasis, a generally fatal parasitic disease, was diagnosed in 2 dogs with a medical history of foreign travel, lymphadenopathy, emaciation, anorexia, intermittent fever, and cutaneous lesions. Clinically, hyperproteinemia, proteinuria, azotemia, and glomerulopathy were evident. Isolation of Leishmania species was done using Schneider's Drosophila medium. Syrian hamsters were used for infectivity studies. Clear taxonomic identification was done biochemically by isoenzyme analysis and comparison of zymogram banding patterns with 6 World Health Organization reference strains. Based on the geographic origin of affected dogs, clinicopathologic presentation, visceralization with hepatosplenomegaly in hamsters, and isoenzyme analysis, a diagnosis of Leishmania leishmania infantum was made. This study, representing the first taxonomic identification of an isolate from canine leishmaniasis, demonstrates the zoonotic and epidemiologic implications of this disease.

Animals↗
PubMedDate not supplied

Inhibition of growth of Leishmania mexicana mexicana by Leishmania mexicana amazonensis during "in vitro" co-cultivation.

Inhibition of one Leishmania subspecies by exometabolites of another subspecies, a phenomenon not previously reported, is suggested by our recent observations in cell cloning experiments with Leishmania mexicana mexicana and Leishmania mexicana amazonensis. Clones were identified using the technique of schizodeme analysis. The phenomenon observed is clearly relevant to studies of parasite isolation, leishmanial metabolism, cross-immunity and chemotherapy.

Animals↗
PubMedDate not supplied

Development of eosinophilia in dogs intradermically inoculated with sand fly saliva and Leishmania (Leishmania) Chagasi stationary-phase promastigotes.

Salivary gland lysates of the sand fly Lutzomia longipalpis have been shown to enhance the infectivity of Leishmania in mice. As shown herein, the simultaneous inoculation of Leishmania chagasi stationary-phase promastigotes and L. longipalpis salivary gland lysate by the intradermal route in a group of mongrel dogs induced a statistically significant eosinophilia, in relation to dogs inoculated with Leishmania or with salivary gland lysate only. These dogs had no evidence of infection, in spite of the high infectivity of the promastigotes when inoculated by the intravenous route.

Animals↗
PubMed2002

Rapid IL-4 production by Leishmania homolog of mammalian RACK1-reactive CD4(+) T cells in resistant mice treated once with anti-IL-12 or -IFN-gamma antibodies at the onset of infection with Leishmania major instructs Th2 cell development, resulting in nonhealing lesions.

Rapid production of IL-4 by Leishmania homolog of mammalian RACK1 (LACK)-reactive CD4(+) T cells expressing the V beta 4-V alpha 8 TCR chains has been shown to drive aberrant Th2 cell development and susceptibility to Leishmania major in BALB/c mice. In contrast, mice from resistant strains fail to express this early IL-4 response. However, administration of either anti-IL-12 or -IFN-gamma at the initiation of infection allows the expression of this early IL-4 response in resistant mice. In this work we show that Leishmania homolog of mammalian RACK1-reactive CD4(+) T cells also expressing the V beta 4-V alpha 8 TCR chains are the source of the early IL-4 response to L. major in resistant mice given anti-IL-12 or -IFN-gamma Abs only at the onset of infection. Strikingly, these cells were found to be required for the reversal of the natural resistance of C57BL/6 mice following a single administration of anti-IL-12 or -IFN-gamma Abs. Together these results suggest that a deficiency in mechanisms capable of down-regulating the early IL-4 response to L. major contributes to the exquisite susceptibility of BALB/c mice to L. major.

Animals↗
PubMed1990

Production of a specific monoclonal antibody for the identification of Leishmania (Leishmania) venezuelensis.

We describe a monoclonal antibody (Mab), V1, specific for Leishmania (Leishmania) venezuelensis. Previous Mabs and DNA probes were not specific for this parasite, and so it was not directly possible to distinguish L. (L.) venezuelensis from other Leishmania species. Immunofluorescent staining using Mabs may be performed on very few parasites, whereas other methods of identification usually require far greater numbers of organisms. L. (L.) venezuelensis frequently dies on subculture. Mab V1 can be used to identify this parasite by indirect immunofluorescence and radioimmunoassay.

Animals↗
PubMed1994

Visceral leishmaniasis in Angola due to Leishmania (Leishmania) infantum.

A 26-year-old man from Angola with no history of travel outside the country presented with typical symptoms of visceral leishmaniasis. The parasite was isolated and biochemically characterized using both kinetoplast DNA and nuclear DNA probes and showed a strong homology with Leishmania (Leishmania) donovani sensu lato (s.l.). When the nuclear DNA of the isolate was hybridized with a specific Leishmania (L.) infantum probe, the pattern obtained showed a clear signal with this species. To establish its identity more specifically, this isolate was typed using a 15-system isoenzyme panel and thick-starch gel electrophoresis, and was identified as L. (L.) infantum zymodeme 1 (MAD-1), the most widespread zymodeme in Mediterranean countries. One case of visceral leishmaniasis has been reported in Angola, but this case is the first report of L. (L.) infantum in Africa south of the equator.

Adult↗
PubMed2004

Characterization of the early cellular immune response to Leishmania major using peripheral blood mononuclear cells from Leishmania-naive humans.

While the response to Leishmania major is well characterized in mice, there is much less known about the human immune response, particularly early after exposure to the parasite. Therefore, we developed a primary in vitro (PIV) system that allowed us to address these questions. We co-cultured peripheral blood mononuclear cells from Leishmania-naive donors with L. major parasites and found that the responding PIV cells produced interferon-gamma and interleukin-12 (IL-12). When restimulated, these PIV cells also occasionally produced IL-5. Both CD4 and CD8 cells and both HLA class I and II cell activation pathways appeared to play a role in the PIV system, and cell activation was dependent upon the presence of antigen-presenting cells. Moreover, PIV cells generated with L. major showed considerable cross-reactivity with other species of Leishmania. Finally, the PIV cells augmented intracellular killing of L. major when they were co-cultured with macrophages infected with the parasite.

Animals↗