Murine cutaneous Leishmaniasis: Comparative study on the capacity of macrophages from “Healer” and “Non-Healer” mouse strains to control L. tropica replication (original) (raw)
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European Journal of Immunology, 1999
We have previously demonstrated that murine macrophages (M ¤ ) infected with Leishmania promastigotes, in contrast to M ¤ infected with the amastigote stage of these parasites, are able to present the Leishmania antigen LACK (Leishmania homologue of receptors for activated C kinase) to specific, I-A d -restricted T cell hybrids and to the T cell clone 9.1-2. These T cells react with the LACK (158-173) peptide, which is immunodominant in BALB/c mice. Here, we show that the level of stimulation of the LACK-specific T cell hybridoma OD12 by promastigote-infected M ¤ is clearly dependent upon the differentiation state of the internalized parasites. Thus, shortly after infection with log-phase or stationary-phase promastigotes of L. major or of L. amazonensis, M ¤ strongly activated OD12. The activity was transient and rapidly lost. However, under the same conditions, activation of OD12 by M ¤ infected with metacyclic promastigotes of L. major or of L. amazonensis was barely detectable. At the extreme, M ¤ infected with amastigotes were incapable to stimulate OD12. Thus, the presentation of LACK by infected M ¤ correlates with the degree of virulence of the phagocytosed parasites, the less virulent being the best for the generation/expression of LACK (158-173)-I-A d complexes. While the intracellular killing of the parasites appears to be an important condition for the presentation of LACK, it is not the only requisite. The partial or total destruction of intracellular L. amazonensis amastigotes does not allow the presentation of LACK to OD12. A preferential interaction of LACK (158-173) with recycling rather than newly synthesized MHC class II molecules does not explain the transient presentation of LACK by M ¤ infected with log-phase or stationary-phase promastigotes because brefeldin A strongly inhibited the presentation of LACK to OD12. Taken together, these results suggest that virulent stages of Leishmania, namely metacyclics and amastigotes, have evolved strategies to avoid or minimize their recognition by CD4 + T lymphocytes. Abbreviations: BFA: Brefeldin A BMDM ¤ : Bone marrowderived M ¤ LACK: Leishmania homologue of receptors for activated C kinase Leu-oMe: L-Leucine methyl ester LPG: Lipophosphoglycan MOI: Multiplicity of infection PV: Parasitophorous vacuole 762 N. Courret et al.
Experimental Parasitology, 1992
amazonensis infection: A comparison of in vivo leishmanicidal mechanisms between immunized and naive infected BALBlc mice. Experimental Parasitology 74, 169-176. In vitro studies have shown that both macrophage activation and destruction of parasitized macrophages lead to leishmania destruction. The relative role played by such mechanisms in vivo have not been properly evaluated. We took advantage of the model of intravenous immunization with solubilized leishmanial antigen which renders partially resistant the otherwise highly susceptible BALB/c mice to address this issue avoiding the interference of different genetic backgrounds. Leishmania destruction occurred in three situations: destruction of the parasitized macrophage, which were in close contact with lymphocytes or eosinophils; extracellular damage, always surrounded by small foci of granulocytes; and parasite damage inside activated macrophages. Destruction of the parasitized macrophages was frequently seen in immunized and protected animals. Our observations suggest that destruction of parasite-loaded macrophages is an important mechanism of host protection in experimental cutaneous leishmaniasis. 0 19% Academic PESS, IX.
Journal of Parasitology, 2010
The antigenic profile and infectivity were compared between 3 recent Leishmania (Viannia) isolates from the Amazonian region (Instituto Nacional de Pesquisas da Amazonia [INPA] strains) and 3 World Health Organization (WHO) reference species (Leishmania guyanensis, Leishmania braziliensis, and Leishmania naiffi). Differences were observed in the peak and extent of promastigote growth. The WHO reference strains exhibited significantly higher exponential growth as promastigotes than INPA strains. In the immunoblot analyses, the INPA strains revealed several specific peptide fragments, as well as the greatest recognition frequencies by sera from Leishmania sp.-infected patients; among the latter, antigens derived from L. naiffi were the most frequently recognized. In vitro infection was carried out using mice peritoneal macrophages; all strains were able to enter the macrophages, but only L. amazonensis was able to reproduce. A striking observation was that L. naiffi exhibited the longest survival time inside the macrophages. Our data strongly suggest the application of recently isolated parasites as sources of antigen for diagnosis procedures. Moreover, L. naiffi species possesses several characteristics relevant for its use as a source of novel antigens to be explored in the design of diagnostic tools and vaccines.
Immunobiology, 2000
Myeloid-related protein (MRP) 14, an intracellular protein involved in calcium-dependent activation of myeloid cells, presents a differentiation marker for a subtype of macrophages. In experimentalleishmaniasis, BALB/c mice succumb to visceral dissemination after infection with L. major, due to a Th2 cell response, while C57Bl/6 mice develop protective immunity associated with a Th1 cell response. We have previously shown that resistance in C57Bl/6 mice was also associated with a significantly lower percentage of MRP14-positive cells in the infiltrate than in susceptible BALB/c mice. In C57B1I6 mice, weekly injections of bone marrow (BM) cells enriched with MRP14-positive cells (d1 of culture) did not reverse, but prolonged the course of infection, associated with increased local parasite spread. In BALB/c mice a single dose of an antiphlogistic agent (dexamethasone or lipoxygenase inhibitor) was associated with reduction of infiltrating MRP 14-positive cells and also with a decrease of parasite loads in footpads, lymph nodes as well as spleens, and with delayed progression of disease. Double labeling experiments in vitro revealed that at least 43.1 % of MRP14-positive mononuclear cells in BM cultures (8h) had phagocytosed parasites after 4 h of co-incubation. Activation by IFN-y (20 U/ml) for 24h and 48h did not significantly reduce parasite load in these cells. In contrast, 77.00/0 of F4/80-positive macrophages (6d of culture) were infected with L. major parasites and these cells responded to activation with IFN-y (20 U/m!) with significant reduction of parasite load (25.3 0/0). The protein MRP14 did not have an effect on parasite survival in vitro. Thus, the impaired capability of MRP 14-positive cells to kill L. major upon stimulation may be one reason for the adverse course of infection observed with their increased appearance.
Infectivity of five different types of macrophages by Leishmania infantum
Leishmania are intracellular parasites that multiply as the amastigote form in the macrophages of their vertebrate hosts. Since vaccines against leishmaniases are still under development, the control of these diseases relies on prompt diagnosis and chemotherapy in infected humans as well as in dogs, which are the main reservoir of Leishmania infantum, in Mediterranean countries.
Effects of heterogeneity of Leishmania tropica isolates in infected human macrophages
：Leishmaniasis is a disease caused by protozoan parasites of the genus Leishmania. The significance of Leishmania tropica (late ulcerative) in human cutaneous leishmaniasis has been recognized only recently, whereas can visceralize and cause systemic illness. Virulence variability was investigated by analyzing the experimental pathogenicity of nine Leishmania tropica strains. BALB/c mice were injected in the hind footpad with metacyclic promastigotes and lesion progression was recorded weekly intervals. Parasite burden, in tissue or draining lymph nodes, was determined by impression smears and limiting-dilution assay. Furthermore, human macrophages were infected with metacyclic promastigotes for 48 and 72 h, afterwards the percentage of infected macrophages and the average numbers of amastigotes per one infected macrophage were determined. A great variety of infection profiles between strains were observed; five strains showed a progressive infection about 5 weeks prior to being controlled (parasite loads in footpads swelling and lymph nodes were 10 4-10 5 and 10 6-10 8 parasites/mg, respectively). One strain produced only moderate and transient swelling, three strains never produced lesions, after which time, nonhealing and nonulcerative lesions persisted for over 6 months. The relationship was observed between profile and growth characterization in vitro. The high virulence strain was characterized by a significantly higher ability to infect human macrophages and to survive with higher replication levels within the infected macrophages. These results suggest that L. tropica isolates from the field may differ in virulence. The characterization of parasite virulence appears to be related to intrinsic parasitic factors that can affect the pathology of leishmaniasis.