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Mechanism of down-regulation of RNA polymerase III-transcribed non-coding RNA genes in macrophages by Leishmania.
Rana T, Misra S, Mittal MK, Farrow AL, Wilson KT, Linton MF, Fazio S, Willis IM, Chaudhuri G
(2011) J Biol Chem 286: 6614-26
MeSH Terms: Animals, Calcium, Calpain, Cell Line, Tumor, Down-Regulation, Humans, Leishmania major, Leishmaniasis, Cutaneous, Macrophages, Metalloendopeptidases, Mice, RNA Polymerase III, RNA, Untranslated, Receptor, PAR-1, Transcription Factors, TFIII
Show Abstract · Added December 10, 2013
The parasitic protozoan Leishmania invades mammalian macrophages to establish infection. We reported previously that Leishmania manipulates the expression of several non-coding RNA genes (e.g. Alu RNA, B1 RNA, and signal recognition particle RNA) in macrophages to favor the establishment of their infection in the phagolysosomes of these cells (Ueda, Y., and Chaudhuri, G. (2000) J. Biol. Chem. 275, 19428-19432; Misra, S., Tripathi, M. K., and Chaudhuri, G. (2005) J. Biol. Chem. 280, 29364-29373). We report here the mechanism of this down-regulation. We found that the non-coding RNA (ncRNA) genes that are repressed by Leishmania infection in macrophages contain a "B-box" in their promoters and thus require the polymerase III transcription factor TFIIIC for their expression. We also found that Leishmania promastigotes through their surface protease (leishmanolysin or gp63) activate the thrombin receptor PAR1 in the macrophages. This activation of PAR1 raised the cytosolic concentration of Ca(2+) into the micromolar range, thereby activating the Ca(2+)-dependent protease μ-calpain. μ-Calpain then degraded TFIIIC110 to inhibit the expression of the selected ncRNA genes. Avirulent stocks of Leishmania not expressing surface gp63 failed to down-regulate ncRNAs in the exposed macrophages. Inhibition of PAR1 or calpain 1 in macrophages made them resistant to Leishmania infection. These data suggest that macrophage PAR1 and calpain 1 are potential drug targets against leishmaniasis.
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15 MeSH Terms
Leukotrienes are essential for the control of Leishmania amazonensis infection and contribute to strain variation in susceptibility.
Serezani CH, Perrela JH, Russo M, Peters-Golden M, Jancar S
(2006) J Immunol 177: 3201-8
MeSH Terms: Animals, Arachidonate 5-Lipoxygenase, Disease Susceptibility, Female, Leishmania mexicana, Leishmaniasis, Cutaneous, Leukotrienes, Macrophages, Mice, Nitric Oxide
Show Abstract · Added May 4, 2017
Leukotrienes (LTs) are known to be produced by macrophages when challenged with Leishmania, but it is not known whether these lipid mediators play a role in host defense against this important protozoan parasite. In this study, we investigated the involvement of LTs in the in vitro and in vivo response to Leishmania amazonensis infection in susceptible (BALB/c) and resistant (C3H/HePAS) mice. Pharmacologic or genetic deficiency of LTs resulted in impaired leishmanicidal activity of peritoneal macrophages in vitro. In contrast, addition of LTB4 increased leishmanicidal activity and this effect was dependent on the BLT1 receptor. LTB4 augmented NO production in response to L. amazonensis challenge, and studies with a NO synthesis inhibitor revealed that NO was critical for the enhancement of macrophage leishmanicidal activity. Interestingly, macrophages from resistant mice produced higher levels of LTB4 upon L. amazonensis challenge than did those from susceptible mice. In vivo infection severity, as assessed by footpad swelling following s.c. promastigote inoculation, was increased when endogenous LT synthesis was abrogated either pharmacologically or genetically. Taken together, these results for the first time reveal an important role for LTB4 in the protective response to L. amazonensis, identify relevant leishmanicidal mechanisms, and suggest that genetic variation in LTB4 synthesis might influence resistance and susceptibility patterns to infection.
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1 Members
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10 MeSH Terms
Leishmaniasis host response loci (lmr1-3) modify disease severity through a Th1/Th2-independent pathway.
Elso CM, Roberts LJ, Smyth GK, Thomson RJ, Baldwin TM, Foote SJ, Handman E
(2004) Genes Immun 5: 93-100
MeSH Terms: Animals, Animals, Congenic, Crosses, Genetic, DNA Primers, Disease Models, Animal, Fluorescence, Genetic Linkage, Genotype, Interferon-gamma, Interleukin-4, Leishmania major, Leishmaniasis, Cutaneous, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Phenotype, Species Specificity, Th1 Cells, Th2 Cells
Show Abstract · Added December 10, 2013
The severity of disease caused by infection with Leishmania major depends critically on the genetics of the host. Early induction of T helper (Th)1-type immune responses in the resistant C57BL/6 mice and Th2-type responses in the susceptible BALB/c mice are thought to determine cure or disease, respectively. We have previously mapped three host response loci in a genetic cross between C57BL/6 and BALB/c mice, and here we show definitively the involvement of these loci in disease severity using animals congenic for each of the loci. Surprisingly, in the late stage of infection when the difference in disease severity between congenic and parental mice was most pronounced, their cytokine profile correlated with the genetic background of the mice and not with the severity of disease. This indicates that the loci that we have mapped are acting by a mechanism independent of Th phenotype.
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1 Members
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19 MeSH Terms
Evaluation of the murine immune response to Leishmania meta 1 antigen delivered as recombinant protein or DNA vaccine.
Serezani CH, Franco AR, Wajc M, Umada Yokoyama-Yasunaka JK, Wunderlich G, Borges MM, Uliana SR
(2002) Vaccine 20: 3755-63
MeSH Terms: Animals, Antibodies, Protozoan, COS Cells, Cell Line, Chemokine CCL7, Chlorocebus aethiops, Cytokines, Female, Leishmania major, Leishmania mexicana, Leishmaniasis, Cutaneous, Leishmaniasis, Diffuse Cutaneous, Mice, Mice, Inbred BALB C, Monocyte Chemoattractant Proteins, Protozoan Proteins, Protozoan Vaccines, Recombinant Proteins, Solubility, T-Lymphocyte Subsets, Th1 Cells, Th2 Cells, Vaccines, DNA, Vaccines, Synthetic
Show Abstract · Added May 4, 2017
The meta 1 gene of Leishmania is conserved across the genus and encodes a protein upregulated in metacyclic promastigotes. Meta 1 constitutive overexpressing mutants show increased virulence to mice. In this paper, both meta 1 recombinant protein and plasmids bearing the meta 1 gene were tested for their antigenicity and potential for inducing protective immunity in mice. Vaccination with the recombinant protein induced a predominant Th2-type of response and did not result in protection upon challenge with live parasites. Surprisingly, the expected reversal to a CD4(+) Th1-type of response upon genetic immunisation by the intramuscular route was not observed. Instead, vaccination with either the meta 1 gene alone or in fusion with the monocyte chemotactic protein (MCP)-3 cDNA induced a Th2-type of response that correlated with lack of protection against infection.
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1 Members
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24 MeSH Terms
A new standard for the assessment of disease progression in murine cutaneous leishmaniasis.
Roberts LJ, Foote SJ, Handman E
(2000) Parasite Immunol 22: 231-7
MeSH Terms: Animals, DNA, Protozoan, Disease Models, Animal, Disease Progression, Leishmania major, Leishmaniasis, Cutaneous, Lymph Nodes, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Polymerase Chain Reaction
Show Abstract · Added December 10, 2013
Infection of mice with Leishmania major has been used both as a model for the cutaneous disease in humans and as a model for the more general control and function of helper T cells in immunity. In both cases, disease patterns and disease progression have been assessed by two complementary methods, lesion size and parasite burden in the draining lymph nodes. We propose a much improved method for the graphical representation of lesion development which conveys more information with better accuracy. We also describe a polymerase chain reaction method for determining parasite burden, which is faster and allows the analysis of larger numbers of experimental animals than the current limiting dilution analysis. Moreover, these methods are equally applicable to other infectious diseases, an obvious one being schistosomiasis.
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1 Members
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11 MeSH Terms
Chromosomes X, 9, and the H2 locus interact epistatically to control Leishmania major infection.
Roberts LJ, Baldwin TM, Speed TP, Handman E, Foote SJ
(1999) Eur J Immunol 29: 3047-50
MeSH Terms: Animals, Antibodies, Protozoan, Chromosome Mapping, Chromosomes, Female, Genes, MHC Class I, H-2 Antigens, Leishmania major, Leishmaniasis, Cutaneous, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Th1 Cells
Show Abstract · Added December 10, 2013
As in other infectious diseases, the outcome of a Leishmania major infection is closely tied to the T helper cell response type; progressive disease is associated with a predominant Th2 lymphocyte response, healing with a Th1 response. In mice, susceptibility is genetically con trolled, with BALB/c (C) mice being susceptible and C57BL/6 (B) mice being resistant. Using a genome-wide scan on two large populations of F2 mice created from these strains, we have shown previously that susceptibility to infection with L. major is controlled by two autosomal loci: lmr1 at the H2 locus, and lmr2 on chromosome 9. Employing a strategy to identify loci that interact, we show here that lmr1 and lmr2 interact synergistically, and we describe a new locus lmr3, lying on the X chromosome, whose effect depends on a specific lmr1 haplotype.
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1 Members
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14 MeSH Terms
Reinfection in American cutaneous leishmaniasis: evaluation of clinical outcomes in the hamster model.
Osorio Y, Gonzalez SJ, Gama VL, Travi BL
(1998) Mem Inst Oswaldo Cruz 93: 353-6
MeSH Terms: Animals, Cricetinae, Disease Models, Animal, Leishmania guyanensis, Leishmania major, Leishmaniasis, Cutaneous, Recurrence, Time Factors
Show Abstract · Added October 26, 2015
There is no clear understanding of the outcome of reinfection in New World cutaneous leishmaniasis, and its role in the relationship to the development of protection or secondary disease. For this reason, reinfection experiments with homologous (Leishmania panamensis-L. panamensis) and heterologous (L. major-L. panamensis) species of leishmaniae were conducted in the hamster model. The different protocols for primary infections prior to the challenge with L. panamensis were as follows: (a) L. major, single promastigote injection, (b) L. major, three booster infections, (c) L. panamensis, followed by antimonial treatment to achieve subclinical infection, (d) L. panamensis, with active lesions, (by antimonial treatment to achieve subclinical infection, (d) L. panamensis, with active lesions, (e) sham infected, naive controls. Although all reinfected hamsters developed lesions upon challenge, animals with active primary lesions due to L. panamensis, and receiving booster infections of L. major had the most benign secondary lesions (58-91% and 69-76% smaller than controls, respectively, P < 0.05). Subclinically infected animals had intermediate lesions (40-64% smaller than controls, P < 0.05), while hamsters which received a single dose of L. major had no significant improvement over controls. Our results suggested that L. major could elicit a cross protective response to L. panamensis, and that the presence and number of amastigotes persisting after a primary infection may influence the clinical outcome of reinfections.
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1 Members
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8 MeSH Terms
A critical, invariant chain-independent role for H2-M in antigen presentation.
Swier K, Brown DR, Bird JJ, Martin WD, Van Kaer L, Reiner SL
(1998) J Immunol 160: 540-4
MeSH Terms: Animals, Antigen Presentation, Antigens, Differentiation, B-Lymphocyte, Disease Susceptibility, HLA-D Antigens, Histocompatibility Antigens Class II, Leishmania major, Leishmaniasis, Cutaneous, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout
Show Abstract · Added December 10, 2013
Antigen presentation by MHC class II (class II) is facilitated by the accessory molecules, invariant chain (Ii) and H2-M. Ii associates with class II during biosynthesis and promotes transport of class II to Ag-loading compartments. One function of H2-M is the removal of Ii fragments from MHC class II. We have previously demonstrated that Ii-deficient mice, unlike class II-deficient mice, are resistant to L. major infection. In the present study, we found that H2-M-deficient (H2-M0) mice were susceptible to progressive infection with L. major. The dispensability of Ii for control of L. major allowed genetic analysis of whether H2-M functions by association with or independently of Ii. In contrast to Ii-deficient (Ii0) mice, Ii0H2-M0 mice were as susceptible to L. major as H2-M0 mice. Thus, H2-M has an essential, Ii-independent function during presentation of microbial pathogens.
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1 Members
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12 MeSH Terms
Resistance to Leishmania major is linked to the H2 region on chromosome 17 and to chromosome 9.
Roberts LJ, Baldwin TM, Curtis JM, Handman E, Foote SJ
(1997) J Exp Med 185: 1705-10
MeSH Terms: Animals, Chromosome Mapping, Genetic Linkage, Genetic Markers, Leishmania major, Leishmaniasis, Cutaneous, Major Histocompatibility Complex, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL
Show Abstract · Added December 10, 2013
In Leishmaniasis, as in many infectious diseases, clinical manifestations are determined by the interaction between the genetics of the host and of the parasite. Here we describe studies mapping two loci controlling resistance to murine cutaneous leishmaniasis. Mice infected with L. major show marked genetic differences in disease manifestations: BALB/c mice are susceptible, exhibiting enlarging lesions that progress to systemic disease and death, whereas C57BL/6 are resistant, developing small, self-healing lesions. F2 animals from a C57BL/6 X BALB/c cross showed a continuous distribution of lesion score. Quantitative trait loci (QTL) have been mapped after a non-parametric QTL analysis on a genome-wide scan on 199 animals. QTLs identified were confirmed in a second cross of 271 animals. Linkage was confirmed to a chromosome 9 locus (D9Mit67-D9Mit71) and to a region including the H2 locus on chromosome 17. These have been named Imr2 and Imr1, respectively.
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1 Members
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10 MeSH Terms