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PubMed2006

Effects of anti-Leishmania monoclonal antibodies on the development of Leishmania major in Phlebotomus duboscqi (Diptera: Psychodidae).

BACKGROUND: Research in our laboratory has previously shown that immune-mediated transmission blocking may be applied to Leishmania infections and that the LPG molecule and anti-LPG monoclonal antibodies was found to be an excellent candidate against L. major infections. OBJECTIVE: To test the effect of monoclonal antibodies (MABs) raised against different species of Leishmania for their ability to inhibit development of Leishmania major in Phlebotomus duboscqi sand flies. DESIGN: A laboratory based study. SETTING: Centre for Biotechnology Research and Development, Kenya Medical Research Institute, Nairobi. RESULTS: Sand fly dissections on days two, four and six post-feeding showed that monoclonal antibodies against L. donovani (Ld2cb and Ld3A3) were the most effective at inhibiting L. major development than those raised against L. aethiopica, L. major or L. tropica. Ld2cb inhibited L. major development by 82% in sand flies fed on 1 x 10(6) amastigotes while Ld3A3 inhibited by 72%; 58% and 74% in those fed on 1 x 10(5) amastigotes respectively. Monoclonal antibodies against L. aethiopica (Lae 3c6) inhibited L. major development by 28% and 40% for sand flies fed on 1 x 10(6) and 1 x 10(5) amastigotes respectively. Anti-L. major monoclonal antibody (Lm5A5) inhibited L. major development by 16% in sand flies fed on 1 x 10(6) amastigotes and 25% in sand flies fed on 1 x 10(5) amastigotes. Anti-L. tropica antibody (Lt2c8) inhibited L. major development in P. duboscqi fed on 1 x 10(6) by 28 %and 33% in those fed on 1 x 10(5) amastigotes. Most of the parasites seen in sand flies which fed on L. donovani mABs (Ld2cb and Ld3A3) were nectomonads and a few haptomonads. In all the control groups, parasite development followed the normal developmental stages up to the metacyclic stage. In sand fly groups fed on monoclonal antibodies raised against L. aethiopica, L. major or L. tropica there was limited parasite development inhibition, and the promastigotes developed and migrated forward in a normal pattern as observed in the controls. CONCLUSIONS: These results suggests a possible role of humoral mechanisms in protection against leishmaniasis and potentially useful in reducing parasite development in the sand fly.

Animals↗
PubMed2006

Relapse of new world diffuse cutaneous leishmaniasis caused by Leishmania (Leishmania) mexicana after miltefosine treatment.

A 35-year-old man with a 19-year history of slowly evolving diffuse cutaneous leishmaniasis was treated with oral miltefosine, 50 mg three times a day. The patient responded after four months of miltefosine treatment with clearance of all nodular lesions and plaques from the entire body surface and had negative slit-skin smears and cultures for Leishmania. However, two months after stopping miltefosine, skin lesions reappeared and parasites were observed in samples. The relapsed lesions did not respond to an additional two-month course of miltefosine. No laboratory or clinical adverse events to miltefosine were observed. Parasites from skin lesions were cultured and identified as Leishmania (Leishmania) mexicana by isoenzyme electrophoresis.

Adult↗
PubMed1991

Metastatic capability of Leishmania (Viannia) panamensis and Leishmania (Viannia) guyanensis in golden hamsters.

The pattern and kinetics of internal dissemination and frequency of cutaneous metastatic lesions resulting from experimental infection of golden hamsters with Leishmania (Viannia) panamensis and Leishmania (Viannia) guyanensis were examined. Nineteen strains were evaluated: 16 L. (V.) panamensis isolated from patients and 3 L. (V.) guyanensis, 2 isolated from human cases and 1 WHO reference strain originating from a sandfly vector. Lymphatic dissemination occurred within 3 mo and was observed for 16 of 16 (100%) of L. (V.) panamensis and 3 of 3 (100%) of L. (V.) guyanensis. Parasites were cultured infrequently from liver and spleen: 3 of 125 (2%) L. (V.) panamensis and 1 of 22 (5%) L. (V.) guyanensis. Decreased frequency of isolation from the inoculation site and draining lymph nodes over time was accompanied by increased frequency of isolation from distant lymph nodes. Dilution of triturated tissue samples resulted in an increased efficiency of parasite culture. Both primary lesions and secondary cutaneous metastatic lesions were more severe in hamsters infected with L. (V.) guyanensis than with L. (V.) panamensis. Cutaneous metastatic lesions were produced more frequently by L. (V.) guyanensis, 24 of 46 hamsters (52%), than by L. (V.) panamensis, 28 of 252 hamsters (11%). Individual Leishmania strains displayed distinctive propensities to produce cutaneous metastases, manifested as a reproducible phenotype. Metastatic pathogenicity was independent of the inoculum dose, supporting the dissociation of infectivity and pathogenicity.

Animals↗
PubMed1985

[Monoclonal antibodies against defined Leishmania antigens protect mice against infection by different species of Leishmania].

Mice monoclonal antibodies (IgG) have been raised against Leishmania infantum promastigotes by fusing SP 2/0 myeloma cells and immunized mice splenic cells. The monoclonal antibodies have been detected by indirect immunofluorescence. In vivo tests showed that some of them could inhibit the life cycle of several Leishmania species from the Old and the New World. Studies of these protective monoclonals by the western blot technique showed the presence of three constant antigens (40 kD, 70 kD and 113 kD) amongst the Leishmania species studied.

Animals↗
PubMed2003

Leishmania mexicana and Leishmania major: attenuation of wild-type parasites and vaccination with the attenuated lines.

A method for attenuation of Leishmania species by culturing in vitro under gentamicin pressure has been used successfully with Leishmania mexicana, L. major, L. infantum, and L. donovani. The attenuated lines invaded but were unable to survive within bone marrow-derived macrophages in vitro, whereas wild-type parasites survived and multiplied. The attenuated lines of L. mexicana and L. major both failed to induce cutaneous lesions in the majority of BALB/c mice over a minimum 12-week observation period after subcutaneous injection of stationary phase parasites. The attenuated line of L. mexicana retained its properties in gentamicin-free medium over 40 subcultures. The attenuated lines of L. mexicana and L. major both induced significant protection in mice against challenge with wild-type parasites.

Animals↗
PubMed2003

Comparison of the A2 gene locus in Leishmania donovani and Leishmania major and its control over cutaneous infection.

In Old World Leishmania infections, Leishmania donovani is responsible for fatal visceral leishmaniasis, and L. major is responsible for non-fatal cutaneous leishmaniasis in humans. The genetic differences between these species which govern the pathology or site of infection are not known. We have therefore carried out detailed analysis of the A2 loci in L. major and L. donovani because A2 is expressed in L. donovani but not L. major, and A2 is required for survival in visceral organs by L. donovani. We demonstrate that although L. major contains A2 gene regulatory sequences, the multiple repeats that exist in L. donovani A2 protein coding regions are absent in L. major, and the remaining corresponding A2 sequences appear to represent non-expressed pseudogenes. It was possible to restore amastigote-specific A2 expression to L. major, confirming that A2 regulatory sequences remain functional in L. major. Although L. major is a cutaneous parasite in rodents and humans, restoring A2 expression to L. major inhibited its ability to establish a cutaneous infection in susceptible BALB/c or resistant C57BL6 mice, a phenotype typical of L. donovani. There was no detectable cellular immune response against L. major after cutaneous infection with A2-expressing L. major, suggesting that the lack of growth was not attributable to acquired host resistance but to an A2-mediated suppression of parasite survival in skin macrophages. These observations argue that the lack of A2 expression in L. major contributed to its divergence from L. donovani with respect to the pathology of infection.

3' Untranslated Regions↗
PubMed2001

Pre-exposure with low-dose UVA suppresses lesion development and enhances Th1 response in BALB/c mice infected with Leishmania (Leishmania) amazonensis.

This study was conducted to determine whether exposing mice to ultraviolet (UV) radiation would alter the pathogenesis of infection with Leishmania (Leishmania) amazonensis (L. amazonensis) which causes progressive cutaneous disease in susceptible mouse strains. BALB/c mice were irradiated with 10 and 30 J/cm(2) UVA on shaved skin of the back from Dermaray (M-DMR-100) for 4 consecutive days before infection with Leishmania promastigotes. The course of disease was recorded by measuring the size of lesions at various times after infection. Mice groups irradiated with UVA 10 and 30 J/cm(2) showed significantly suppressed lesion development compared with the non-irradiated mice. Light and electron microscopy revealed a few parasites at the site of inoculation in UVA-irradiated subjects. Sandwich enzyme-linked-immunosorbent-assay (ELISA) examination of sera showed dose dependently upregulated interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-12, and downregulated interleukin (IL)-4 and interleukin (IL)-10 levels in UVA-irradiated as compared with the non-irradiated mice. Positive signals for IFN-gamma mRNA in irradiated mice were obtained by RT-PCR, while non-irradiated mice showed negative results. None of the examined samples showed signal for IL-4 mRNA. The present study disclosed that exposure of mice to different low-doses of UVA irradiation prior to infection may interfere with immunity to L. amazonensis in the murine model. This indicates that the cell-mediated response switch from Th2 to Th1 pattern suppressed the cutaneous lesions of L. amazonensis.

Animals↗
PubMedDate not supplied

[Histopathology of the localized form of cutaneous leishmaniasis caused by Leishmania (Leishmania) amazonensis].

The microscopic changes found in the localized form of the human cutaneous leishmaniasis due to Leishmania (Leishmania) amazonensis are reported. In this form, less known than the diffuse one caused by the same species, the clinical manifestations are identical to those produced by other Leishmania species of the subgenus Viannia. There is, however, in the localized infection by L. (L.) amazonensis, a peculiar feature, only recently discovered: about 50% of the affected individuals are Montenegro-negatives. The main histologic change observed in the skin sections was the presence of groups of macrophages with a large vacuole in the cytoplasm, containing many amastigotes. The microscopic picture is similar to that found in the diffuse form of the disease, the difference being only quantitative. When in large numbers, the macrophages suffers necrosis, which generally starts at the center of the groups. First, in this process, the membrane of the parasitized cells ruptures, and the amastigotes become free; later, both cells and parasites are destroyed. The picture can be seen either in Montenegro-negative or in Montenegro-positive patients. The macrophages with amastigotes may persist in tissues for as long as 6-7 months, while in the infections due to L. (V.) braziliensis the parasites usually disappear in a few weeks.

Adolescent↗
PubMed1997

Interleukin-10 and interleukin-4 inhibit intracellular killing of Leishmania infantum and Leishmania major by human macrophages by decreasing nitric oxide generation.

The host response to Leishmania infection is regulated by a specific pattern of local cytokine production. We investigated the effect of interleukin (IL)-10 and IL-4 on the leishmanicidal activity of human macrophages (M phi). As with L. major, intracellular killing of L. infantum by human M phi was obtained following ligation of surface CD23 or cell treatment with interferon-gamma (IFN-gamma). This leishmanicidal activity required nitric oxide (NO) generation by activated M phi, and it was partially mimicked by cell treatment with chemical NO donors. Addition of recombinant human IL-10 or IL-4 to CD23 mAb or IFN-gamma decreased L. infantum and L. major killing by infected M phi. IL-10 was more potent than IL-4 in inhibiting the leishmanicidal activity of human M phi. Inhibition of Leishmania killing by IL-4 and IL-10 correlated with decreased NO generation from M phi, and was reversed when exogenous NO was added to cell cultures. Therefore, IL-10 and IL-4 down-regulate leishmanicidal activity of human M phi, in part by inhibiting NO generation by these cells.

Animals↗
PubMed1996

T-cell responsiveness of American cutaneous leishmaniasis patients to purified Leishmania pifanoi amastigote antigens and Leishmania braziliensis promastigote antigens: immunologic patterns associated with cure.

Patients suffering from American cutaneous leishmaniasis were studied before therapy (active lesion) and at the end of therapy (cured patients). Assays of lymphocyte proliferative responses of peripheral blood mononuclear cells induced in vitro by Leishmania braziliensis promastigote antigens (Lb) or by three proteins (A-2/P-2, P-4, and P-8) derived from Leishmania pifanoi amastigotes were performed. Antigen-stimulated cells were harvested for CD4 and CD8 phenotype analysis and the levels of gamma interferon (IFN-gamma), interleukin 2 (IL-2) and interleukin 4 (IL-4) produced were also determined. Results show two different patterns of Lb-induced T cell responses: (a) predominance of responding CD4+ cells and mixed type 1 and type 2 cytokine production (IFN-gamma, IL-2, and IL-4) during the active disease, (b) similar proportions of responding CD4+ and CD8+ cells and type 1 cytokine production (presence of IFN-gamma and IL-2 and very low IL-4) at the end of therapy (healed lesions). Thus, this last pattern is probably associated with a beneficial T cell response. The A-2/P-2 amastigote cysteine proteinase provided only marginal (s.i. approximately or = 2.5) T cell stimulation in 25% of patients studied; in contrast, the L. pifanoi P-4 and P-8 amastigote antigens induced significant stimulation (s.i. approximately or = 5) in approximately 50% of the patients. In comparison to Lb-stimulated cultures, lower proliferative responses of T lymphocytes to P-4 or P-8 were observed. However, the P-4- or P-8-stimulated cultures had similar percentages of reactive CD4+ and CD8+ cells, as well as type 1 cytokines (presence of IFN-gamma and IL-2, and low levels or absence of IL-4) in the supernatants both before and at the end of therapy. The consistent induction of apparently beneficial T cell responses by the P-4 and P-8 amastigote glycoproteins points to the possibility that these molecules be considered as candidates for future defined vaccines against leishmaniasis.

Animals↗
PubMed1997

Heterologous protection by Leishmania donovani for Leishmania major infections in the vervet monkey model of the disease.

The study was aimed at analyzing immunological cross-reactivity between Leishmania major and Leishmania donovani and possible cross-protection between the two parasite species in the vervet monkey model of the disease. Nine vervet monkeys (Cercopithecus aethiops) from the institute animal colony were sued in the study. Five of the animals had been previously infected with L. donovani but had remained asymptomatic while the other four animals were naive and comprised the control group. Immunological responses to both L. major and L. donovani antigens in the five animals with prior exposure to L. donovani were examined before challenge. High antibody titers to the two antigens were demonstrated in an enzyme-linked immunosorbent assay, but the antibody titers to L. donovani were significantly higher than those to L. major (P < 0.005). Positive in vitro peripheral blood leucocyte (PBL) proliferation to L. major and L. donovani antigens was also demonstrated, but there was no significant difference in the response to the two antigens (P > 0.1). High and varying levels of interferon gamma (IFN-gamma) were secreted in PBL from the five vervet monkeys when stimulated with L. major antigen, but vervet monkey 1296 secreted marginal levels of IFN-gamma. When the animals were challenged intradermally with 1 x 10(5) virulent L. major promastigotes mixed with sandfly vector salivary gland lysate all four vervet monkeys in the control group developed nodules of varying sizes at the inoculation sites that eventually ulcerated. However, nodule formation and ulceration occurred at different times among these animals. The other five animals (animals with prior exposure to L. donovani) did not pick up the infection at all, but one animal from this group, vervet monkey 1296, developed a transient lesion that healed within 9 weeks, the same animal that had been shown to secrete low levels of IFN-gamma. The results demonstrate high cross-reactivity between L. donovani and L. major and that L. donovani protects against L. major infections. This finding is important for vaccine development studies against leishmaniasis.

Animals↗
PubMed1986

Protein methylation and protein methylases in Leishmania donovani and Leishmania tropica promastigotes.

We studied the content of acid-stable methylated amino acids of soluble proteins in promastigotes of Leishmania donovani and L. tropica. epsilon-N-Trimethyllysine and NG,NG-dimethylarginine were found in both Leishmania species after culture in the presence of [methyl-14C]methionine. In addition, 3-N-methylhistidine was found only in L. tropica and epsilon-N-dimethyllysine only in proteins of L. donovani. As sinefungin, an antileishmanial nucleoside antibiotic, is a known transmethylase inhibitor, its effect on protein methylation was studied, in whole cells and in vitro. In the first case the drug had no effect on the content of methylated amino acid residues of soluble proteins. In vitro, histone methylation by crude extracts was studied at pH 7.2 and 9.0, known in other organisms as optimum pH values for arginine and lysine methylation, respectively. Surprisingly, arginine methylation by extracts of L. donovani was the same at both pH values while lysine residues were more efficiently methylated at pH 7.2 than at pH 9 by the extracts of the two species. These results indicate that the properties of protein methylases I and III of these parasites are different from those of other organisms hitherto studied. The inhibition constants of sinefungin for the leishmanial protein methylases were weak in comparison with those for enzymes from other sources, with the exception of the constant of L. donovani enzyme at pH 9.

Adenosine↗
PubMed1987

Characterization of RNA from Leishmania tropica and Leishmania d.donovani promastigotes.

RNA has been prepared from promastigotes of Leishmania tropica and Leishmania d.donovani using three different methods. Extraction by hot phenol/isothiocyanate gave the best quantitative and qualitative results. The analysis of total RNA on methyl mercuric agarose gels shows that the large rRNA species is nicked: it is composed of a 630 and a 560 kDa molecule. The small rRNA species has a molecular weight of 800,000. Poly(A+) RNA can be translated in a rabbit reticulocyte lysate system. The newly synthesized products comprise high molecular weight proteins and show different patterns using RNA from L. tropica or from L. d. donovani promastigotes.

Animals↗
PubMed1989

Presence and properties of cAMP phosphodiesterase from promastigote forms of Leishmania tropica and Leishmania donovani.

1. This paper reports the isolation and the partial purification of cAMP phosphodiesterase (EC 3.1.4.17) from the promastigote form of Leishmania tropica and a preliminary result from Leishmania donovani. 2. The activity of the fraction obtained from column chromatography was measured. 3. The effects of pH, temperature, time of incubation and various compounds on its activity in vitro were obtained. 4. Two peaks (I and II) exhibiting cyclic nucleotide phosphodiesterase activity were obtained. 5. Both activities were found to require the addition of Mg2+ ions for full effect. 6. The apparent Km values for the first and second peaks were 1.43 x 10(-3) M and 4.1 x 10(-3) M respectively. L. donovani shows only one peak of activity.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Leishmania major and Leishmania tropica: I the in vitro effects of an immunomodulator, S2-Complex.

This study was undertaken to try to determine the possible anti-leishmanial activity of S2-Complex, an organic complex of copper chloride, ascorbic acid, and nicotinamide. The promastigotes, axenic amastigotes, and intracellular amastigotes of both Leishmania major and Leishmania tropica were incubated with different concentrations of S2-Complex. The EC50 for each form was calculated. Results show that all forms of the parasites were dose dependently inhibited by S2-Complex. The promastigotes of both parasites were the most resistant with highest EC50 followed by axenic amastigotes. While intracellular amastigotes were the most sensitive with the lowest EC50. These results indicate that S2-Complex has a direct anti-leishmanial effect. When mice were treated with S2-Complex or BCG for four days before harvesting the macrophages, and the macrophages infected with both L. major and L. tropica, they showed increased phagocytosis and increased parasite killing. The results of S2-Complex were not statistically different from the immunomodulating agent BCG. These results indicate that S2-Complex has an immunomodulating effect in addition to the direct anti-leishmanial effect.

Animals↗
PubMed2006

Activity of an engineered synthetic killer peptide on Leishmania major and Leishmania infantum promastigotes.

This study was undertaken to analyze the effect of an engineered, killer decapeptide (KP) on Leishmania major and Leishmania infantum promastigotes. The KP was synthesized on the basis of the sequence of a recombinant, single-chain anti-idiotypic antibody acting as a functional internal image of a yeast killer toxin. The evaluation of in vitro inhibitory activity of KP on L. major and L. infantum, release of intracellular green fluorescent protein (GFP) molecules by L. major, DNA fragmentation, and ultrastructural analysis (TEM) of L. infantum upon KP treatment were performed. KP presented antiproliferative and leishmanicidal activity with LC(50)/1 day of 58 and 72 microM for L. major and L. infantum, respectively. A dose-dependent decrease in proliferation and increase of killing of promastigotes was seen after KP treatment. No DNA fragmentation in L. infantum promastigotes or release of intracellular GFP molecules on peptide treatment of a GFP expressing L. major clone was demonstrated. Moreover the plasma-membrane was not disrupted, but, by TEM analysis, intracellular damage was observed.

Animals↗
PubMed2002

Distinguishing Leishmania tropica and Leishmania major in the Middle East using the polymerase chain reaction with kinetoplast DNA-specific primers.

This paper reports attempts to develop a sensitive and inexpensive procedure for rapid diagnosis of cutaneous leishmaniasis at the species level using skin scrapings from patients. The presence of 3 species (Leishmania major, L. tropica and L. infantum) in Israel and the West Bank demonstrates the need for a species-specific detection method in this region. The primer pair Uni21/Lmj4 was developed on the basis of an L. major minicircle sequence but it also amplified other 'Old World' species of Leishmania. Due to species-specific differences in the size of minicircles, these primers can be used in the polymerase chain reaction to answer diagnostic and epidemiological questions.

Adult↗
PubMed2005

Synthesis of proteophosphoglycans of Leishmania major and Leishmania mexicana.

A novel approach for the synthesis of various fragments of proteophosphoglycans from Leishmania major and Leishmania mexicana proteophosphoglycans has been developed. These compounds have been obtained by coupling alpha-mannosyl and alpha-N-acetyl-glucosamine phosphoramidite derivatives with the serine hydroxyl of various amino acids and peptides to give, after oxidation with tert-BuOOH, phosphotriesters exclusively as alpha-anomers in good yield. The resulting compounds could be deblocked using conventional methods. Glycophosphorylation of preassembled and properly protected peptides was found to be more efficient for the preparation of proteophosphoglycan fragments than a building block approach strategy using a phosphoglycosylserine derivative.

Animals↗