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    Date: Wed, 29 Sep 2004 13:03:07
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REQUEST: [ leishmaniasis ]

(15 articles match this request)



PMID: 15380780
 

TITLE: Requirements for Th1-dependent immunity against infection with Leishmania
major.

AUTHORS: Esther Von Stebut, Mark C Udey

AFFILIATION: Department of Dermatology, Johannes Gutenberg-University,
Langenbeckstrasse 1, D-55101 Mainz, Germany.

REFERENCE: Microbes Infect 2004 Oct 6(12):1102-9

Protective immunity against cutaneous leishmaniasis is dependent on the 
induction of Th1/Tc1 immune responses resulting in efficient parasite 
elimination. In this review, the mechanisms leading to protection are 
discussed with special focus on the role of Leishmania major-infected 
dendritic cells (DC) in induction of Th1-dependent immunity. Murine 
strain-dependent differences between DC derived from Leishmania-
susceptible as compared to resistant mice are highlighted.








PMID: 15379987
 

TITLE: CD4 CCR5 and CD4 CCR3 lymphocyte subset and monocyte apoptosis in
patients with acute visceral leishmaniasis.

AUTHORS: Marcella Potestio, Pietro D'Agostino, Giuseppina Colonna Romano,
Salvatore Milano, Viviana Ferlazzo, Alessandra Aquino, Gloria Di Bella, Rosalba
Caruso, Giuseppe Gambino, Giustina Vitale, Serafino Mansueto, Enrico Cillari

AFFILIATION: Department of BioPathology and BioMedical Methodologies, University
of Palermo, Palermo, Italy.

REFERENCE: Immunology 2004 Oct 113(2):260-8

Summary The potential involvement of apoptosis in the pathogenesis of 
visceral leishmaniasis (VL) was examined by studying spontaneous and 
Leishmania antigen (LAg)-induced apoptosis using cryopreserved 
peripheral blood mononuclear cells (PBMC) of Sicilian patients with VL. 
Results indicate that monocytes and T lymphocytes from acute VL patients
 show a significantly higher level of apoptosis compared with that 
observed in healed subjects. The percentage of apoptotic cells was 
higher in monocytes than in T lymphocytes. T cells involved in 
programmed cell death (PCD) were mainly of the CD4(+) phenotype. In 
particular, the T helper 1-type (Th1) subset, as evaluated by chemokine 
receptor-5 (CCR5) expression, is involved in this process. Cell death in
 Th1-type uses a CD95-mediated mechanism. Furthermore, Th1-type CCR5(+) 
cells are prone to cell suicide in an autocrine or paracrine way, as 
attested by enhanced expression of CD95L in acute VL patients. The 
reduction in Th1-type cells by apoptosis was confirmed by the decrease 
in interferon-gamma secretion. In conclusion, apoptosis of monocytes, 
CD4(+) and CD4(+) CCR5(+) T cells could be involved in the failure of 
cell mediated immunity that is responsible for severe immune-depression 
in VL.




PMID: 15380533
 

TITLE: Leishmania infantum enhances human immunodeficiency virus type-1
replication in primary human macrophages through a complex cytokine network.

AUTHORS: Chenqi Zhao, Barbara Papadopoulou, Michel J Tremblay

AFFILIATION: Laboratory of Human Immuno-Retrovirology, Research Center in
Infectious Diseases, RC709, CHUL Research Center, Quebec (QC), Canada, G1V 4G2;
Faculty of Medicine, Laval University, Quebec, Canada.

REFERENCE: Clin Immunol 2004 Oct 113(1):81-8

Leishmaniasis has emerged as an important potential opportunistic 
disease among patients infected with human immunodeficiency virus type-1
 (HIV-1). It has been reported that the visceral form of leishmaniasis 
accelerates the course of HIV-1 disease progression and shortens the 
life expectancy of persons in areas where both diseases are endemic. As 
both pathogens can infect in a productive manner the same target cell, 
that is, the macrophage, we examined the possible modulatory effect of 
the protozoan parasite Leishmania infantum on the biology of HIV-1 in 
primary human monocyte-derived macrophages (MDMs). We found that 
coinfection of MDMs with Leishmania and HIV-1 resulted in a significant 
enhancement of both virus transcription and release of progeny virus. 
The Leishmania-directed increase in HIV-1 production was associated with
 an increased secretion of the proinflammatory cytokines TNF-alpha and 
IL-1alpha. Altogether, these findings indicate that the presence of 
Leishmania and HIV-1 within the same cellular microenvironment leads to 
an enhancement of virus gene expression. The present work also 
underscores the importance of studying the possible complex interactions
 between two human pathogens in a physiological cellular reservoir.




PMID: 15322192
 

TITLE: Inhibition of lipopolysaccharide-induced macrophage IL-12 production by
Leishmania mexicana amastigotes: the role of cysteine peptidases and the
NF-kappaB signaling pathway.

AUTHORS: Pamela Cameron, Adrienne McGachy, Mary Anderson, Andrew Paul, Graham H
Coombs, Jeremy C Mottram, James Alexander, Robin Plevin

AFFILIATION: Department of Immunology, Strathclyde Institute for Biomedical
Sciences, University of Strathclyde, Glasgow, United Kingdom.

REFERENCE: J Immunol 2004 Sep 173(5):3297-304

Infection with lesion-derived Leishmania mexicana amastigotes inhibited 
LPS-induced IL-12 production by mouse bone marrow-derived macrophages. 
This effect was associated with expression of cysteine peptidase B (CPB
) because amastigotes of CPB deletion mutants had limited ability to 
inhibit IL-12 production, whereas preincubation of cells with a CPB 
inhibitor, cathepsin inhibitor IV, was able to suppress the effect of 
wild-type amastigotes. Infection with wild-type amastigotes resulted in 
a time-dependent proteolytic degradation of IkappaBalpha and IkappaBbeta
 and the related protein NF-kappaB. This effect did not occur with 
amastigotes of CPB deletion mutants or wild-type promastigotes, which do
 not express detectable CPB. NF-kappaB DNA binding was also inhibited by
 amastigote infection, although nuclear translocation of cleaved 
fragments of p65 NF-kappaB was still observed. Cysteine peptidase 
inhibitors prevented IkappaBalpha, IkappaBbeta, and NF-kappaB 
degradation induced by amastigotes, and recombinant CPB2.8, an 
amastigote-specific isoenzyme of CPB, was shown to degrade GST-
IkappaBalpha in vitro. LPS-mediated IkappaBalpha and IkappaBbeta 
degradation was not affected by these inhibitors, confirming that the 
site of degradation of IkappaBalpha, IkappaBbeta, and NF-kappaB by the 
amastigotes was not receptor-driven, proteosomal-mediated cleavage. 
Infection of bone marrow macrophages with amastigotes resulted in 
cleavage of JNK and ERK, but not p38 MAPK, whereas preincubation with a 
cysteine peptidase inhibitor prevented degradation of these proteins, 
but did not result in enhanced protein kinase activation. Collectively, 
our results suggest that the amastigote-specific cysteine peptidases of 
L. mexicana are central to the ability of the parasite to modulate 
signaling via NF-kappaB and consequently inhibit IL-12 production.




PMID: 15378809
 

TITLE: Leishmaniasis.

AUTHORS: Philippe Desjeux

REFERENCE: Nat Rev Microbiol 2004 Sep 2(9):692




PMID: 15380274
 

TITLE: Purification, characterization of O-acetylated
sialoglycoconjugates-specific IgM, and development of an enzyme-linked
immunosorbent assay for diagnosis and follow-up of indian visceral
leishmaniasis patients.

AUTHORS: Sumi Bandyopadhyay, Mitali Chatterjee, Santanu Pal, Ross F Waller,
Shyam Sundar, Malcolm J McConville, Chitra Mandal

AFFILIATION: Immunobiology Division, Indian Institute of Chemical Biology,
Jadavpur, Kolkata, India.

REFERENCE: Diagn Microbiol Infect Dis 2004 Sep 50(1):15-24

The surface expression of 9-O-acetylated sialic acid (9-OAcSA) is 
elevated on hematopoietic cells and erythrocytes of visceral 
leishmaniasis (VL) patients. In this study, we show that VL patients 
contain elevated levels of IgM antibodies directed against 9-O-
acetylated sialoglycoconjugates (9-OAcSG). These antibodies were 
affinity purified with bovine submaxillary protein as the affinity 
matrix containing the terminal epitope, 9-OAcSAalpha2-6GalNAc. They also
 bound to 9-OAcSGs on hematopoietic cells of patients with VL and to 
epitopes in the cytosol of Leishmania donovani promastigotes. A novel 
enzyme-linked immunosorbent assay was employed that showed 4-fold higher
 anti-OAcSG titers in VL patients (n = 38), mean +/- S.E.M. being 0.83
 +/- 0.09 vs. 0.21 +/- 0.04 detected in normal donors (n = 20) and 
patients with cross-reactive diseases such as malaria (n = 4) or 
tuberculosis (n = 4). Assay specificity and sensitivity was 100% and 92
%, respectively, whereas positive and negative predictive values were 
100% and 90%, respectively. Significantly, anti-OAcSG titers declined 30
 days after completion of anti-leishmanial treatment, indicating that 
monitoring of anti-9-OAcSGs may be a valuable alternative toward 
increasing the efficiency of diagnosis and follow-up of VL.




PMID: 15322011
 

TITLE: Chemokine gene expression in toll-like receptor-competent and -deficient
mice infected with Leishmania major.

AUTHORS: Simone Antoniazi, Helen P Price, Pascale Kropf, Marina A Freudenberg,
Chris Galanos, Deborah F Smith, Ingrid Müller

AFFILIATION: Imperial College London, Faculty of Medicine, Department of
Immunology, Norfolk Place, London W2 1PG, United Kingdom.

REFERENCE: Infect Immun 2004 Sep 72(9):5168-74

We studied the expression of a subset of chemokines, including RANTES/
CCL5, MIP-1alpha/CCL3, IP-10/CXCL10, and MCP-1/CCL2, in Toll-like 
receptor (TLR)-competent and -deficient mice after infection with 
Leishmania major. Chemokine expression at the site of infection (the 
footpad), in the draining lymph nodes and in the spleens of infected 
animals was determined by using two different methods of analysis. The 
results indicate that L. major infection causes overall upregulation of 
RANTES/CCL5, MIP-1alpha/CCL3, IP-10/CXCL10, and MCP-1/CCL2 in the 
footpads and lymph nodes, while expression of these chemokines is 
constitutive in the spleens of TLR4-competent mice (C57BL/10ScSn) and 
TLR4-deficient mice (C57BL10/ScN). Different patterns of expression were
 detected depending on the time postinfection, but there was little 
variation in the expression of these four chemokines in the presence or 
absence of TLR4.








PMID: 15252045
 

TITLE: Dual action of antimonial drugs on thiol redox metabolism in the human
pathogen Leishmania donovani.

AUTHORS: Susan Wyllie, Mark L Cunningham, Alan H Fairlamb

AFFILIATION: Division of Biological Chemistry and Molecular Biology, Wellcome
Trust Biocentre, School of Life Sciences, University of Dundee, Dundee DD1 5EH,
Scotland.

REFERENCE: J Biol Chem 2004 Sep 279(38):39925-32

Despite extensive use of antimonial compounds in the treatment of 
leishmaniasis, their mode of action remains uncertain. Here we show that
 trivalent antimony (Sb(III)) interferes with trypanothione metabolism 
in drug-sensitive Leishmania parasites by two inherently distinct 
mechanisms. First, Sb(III) decreases thiol buffering capacity by 
inducing rapid efflux of intracellular trypanothione and glutathione in 
approximately equimolar amounts. Second, Sb(III) inhibits trypanothione 
reductase in intact cells resulting in accumulation of the disulfide 
forms of trypanothione and glutathione. These two mechanisms combine to 
profoundly compromise the thiol redox potential in both amastigote and 
promastigote stages of the life cycle. Furthermore, we demonstrate that 
sodium stibogluconate, a pentavalent antimonial used clinically for the 
treatment for leishmaniasis, induces similar effects on thiol redox 
metabolism in axenically cultured amastigotes. These observations 
suggest ways in which current antimony therapies could be improved, 
overcoming the growing problem of antimony resistance.




PMID: 15364993
 

TITLE: Isoenzymatic analysis of 712 strains of Leishmania infantum in the south
of France and relationship of enzymatic polymorphism to clinical and
epidemiological features.

AUTHORS: Francine Pratlong, Jean-Antoine Rioux, Pierre Marty, Françoise
Faraut-Gambarelli, Jacques Dereure, Geneviève Lanotte, Jean-Pierre Dedet

AFFILIATION: Laboratoire de Parasitologie-Mycologie and Centre National de
Référence des Leishmania, CHU de Montpellier, France.

REFERENCE: J Clin Microbiol 2004 Sep 42(9):4077-82

In the south of France, leishmaniasis due to Leishmania infantum occurs 
in the following five foci of endemicity (from west to east): Pyrénées
-Orientales, Cévennes, Provence, Côte d'Azur, and Corsica. Between 
1981 and 2002, 712 Leishmania strains obtained from humans, dogs, cats, 
and sand flies were studied by isoenzyme analysis. In total, seven 
zymodemes were identified: MON-1, MON-11, MON-24, MON-29, MON-33, MON-34
, and MON-108. The Pyrénées-Orientales focus is characterized by a 
predominance of human cutaneous leishmaniasis and a high enzymatic 
polymorphism (five zymodemes). In the other foci, where human visceral 
leishmaniasis is predominant, only two zymodemes are present. L. 
infantum MON-1 is the parasite most frequently found, in patients both 
with and without concomitant human immunodeficiency virus infection. MON
-1 is the only zymodeme present in dogs, which act as the reservoir host
 in all of the foci. In Cévennes, where the complete life cycle of 
zymodeme MON-1 has been identified, Phlebotomus perniciosus and 
Phlebotomus ariasi are vectors. The enzymatic polymorphism is compared 
to that of neighboring countries (Spain and Italy). In Pyrénées-
Orientales, small variant zymodemes with electromorphs of heterozygote-
like and homozygotic patterns can be explained by different genetic 
hypotheses.




PMID: 15381810
 

TITLE: Cross-immunity experiments between different species or strains of
Leishmania in rhesus macaques (Macaca mulatta).

AUTHORS: Renato Porrozzi, Antonio Teva, Veronica F Amaral, Marcos V Santos da
Costa, Gabriel Grimaldi

AFFILIATION: Departments of Immunology and Ultrastructural and Cell Biology,
Instituto Oswaldo Cruz/FIOCRUZ, Rio de Janeiro, Brazil.

REFERENCE: Am J Trop Med Hyg 2004 Sep 71(3):297-305

This study evaluates cross-immunity in rhesus monkeys (Macaca mulatta) 
previously infected with one species of Leishmania and have had self-
cured disease or were cured by antimony-based therapy upon development 
of full-blown disease. We found that a self-healing cutaneous 
leishmaniasis (CL) following experimental infection with Leishmania (
Leishmania) major induces significant protection for L. (L.) amazonensis
 and L. (Viannia) guyanensis, and was dependent on time of re-challenge 
by L (L.) amazonensis after animals had recovered from primary lesions, 
but lacked protection against L. (V.) braziliensis. In contrast, monkeys
 that recovered from L. (V.) braziliensis CL or L. (L.) chagasi visceral
 leishmaniasis following chemotherapeutic intervention were protected by
 challenge with L. (V.) braziliensis and L (L.) amazonensis. These 
findings indicate the relative variability in protection after self-cure
 or drug-cured experimental leishmaniasis to challenge by heterologous 
leishmanial parasites. Further studying the immune response may provide 
information regarding relevant factors influencing cross-protective 
immunity.




PMID: 15382405
 

TITLE: WHO action in Afghanistan aims to control debilitating leishmaniasis.

REFERENCE: Wkly Epidemiol Rec 2004 Aug 79(35):319-20




PMID: 15125539
 

TITLE: Coinfection with Listeria monocytogenes potentlxtes the response of
BALB/c mice against Leishmania major.

AUTHORS: Khaled S Tabbara, Ahmad S Al-Azmi, Jawaher A Al Salem

AFFILIATION: Department of Microbiology, Immunology and Infectious Diseases,
College of Medicine, Arabian Gulf University, Manama, Bahrain.
tabara at agu.edu.bh

REFERENCE: J Egypt Soc Parasitol 2004 Apr 34(1):349-66

Protection against L. major is dependent on the stimulation of an anti-
leishmanial T helper1 (Th1) response and the production of Interferon (
IFN)-y. BALB/c mice develop a Th2 response and fatal infection with 
Leishmania major. Strategies that boost IL-12 production have shown to 
be protective. The innate response to Listeria monocytogenes is 
associated with IL-12 production. The co-infection of BALB/c mice with L
. monocytogenes attenuates the course of L. major infection. Lesion 
sizes were smaller, and co-infected mice out-survived controls injected 
with L. major alone. The parasite load was reduced at site of injection
, in draining lymph nodes (LN) and spleen. During the first week of 
infection, in-vitro Leishmania-restimulated LN cells from co-infected 
mice produced higher levels of IFN-7 and undetectable levels of IL-4 
compared to controls. Significant IL-4 mRNA expression was detected in 
LN cells of control but not in co-infected mice.








PMID: 15382468
 

TITLE: [Relapse of visceral leishmaniasis in HIV infection. Benefit of
amphotericin B]

AUTHORS: Badreddine Kilani, Lamia Amari, Slah Belhaj, Ahmed Goubontini, Taoufik
Ben Chaabene

AFFILIATION: Service des maladies infectieuses, Hôpital la Rabta, Tunis,
Tunisie.

REFERENCE: Tunis Med 2004 Mar 82(3):316-9

The reference treatment in visceral leishmaniasis is administration of 
antimonial compounds. Failures have been reported particularly in HIV-
positive patients. The authors describe the case of a 40-year-old 
patient who, after 2 courses of N-methyl-glucamine, relapsed. Bone 
marrow cultures became negative only after adminstration of amphotericin
 B (1 mg x kg x d) for 28 days. He is still asymptomatic 18 months after
 he was cured. Amphotericin B, in case of relapse, seems to be a 
valuable alternative, until the availability of the liposomal form in 
our country.




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PMID: 12019027
 

TITLE: In vitro susceptibility to pentavalent antimony in Leishmania infantum
strains is not modified during in vitro or in vivo passages but is modified
after host treatment with meglumine antimoniate.

AUTHORS: Jaume Carrió, Montserrat Portús

AFFILIATION: Laboratory of Parasitology, Departament de Microbiologia i
Parasitologia Sanità ries, Facultat de Farmà cia, Universitat de Barcelona,
08028 Barcelona, Spain. jcarrio at farmacia.far.ub.es

REFERENCE: BMC Pharmacol 2002 May 2(1):11

BACKGROUND: Leishmaniasis is a common parasitic disease in Southern 
Europe, caused by Leishmania infantum. The failures of current treatment
 with pentavalent antimonials are partially attributable to the 
emergence of antimony-resistant Leishmania strains. This study analyses 
the in vitro susceptibility to pentavalent antimony of intracellular 
amastigotes from a range of L. infantum strains, derived from the same 
infected animal, during in vitro and in vivo passages and after host 
treatment with meglumine antimoniate. RESULTS: SbV-IC50 values for 
strains from two distinct isolates from the same host and one stock 
after two years of culture in NNN medium and posterior passage to 
hamster were similar (5.0 +/- 0.2; 4.9 +/- 0.2 and 4.4 +/- 0.1 mgSbV/L, 
respectively). In contrast, a significant difference (P < 0.01, t 
test) was observed between the mean SbV-IC50 values in the stocks 
obtained before and after treatment of hosts with meglumine antimoniate
 (4.7 +/- 0.4 mgSbV/L vs. 7.7 +/- 1.5 mgSbV/L). Drug-resistance after 
drug pressure in experimentally infected dogs increased over repeated 
drug administration (6.4 +/- 0.5 mgSbV/L after first treatment vs. 8.6
 +/- 1.4 mgSbV/L after the second) (P < 0.01, t test). CONCLUSIONS: 
These results confirm previous observations on strains from Leishmania/
HIV co-infected patients and indicate the effect of the increasing use 
of antimony derivatives for treatment of canine leishmaniasis in endemic
 areas on the emergence of Leishmania antimony-resistant strains.




PMID: 9820738
 

TITLE: Host susceptibility factors to cutaneous leishmaniasis.

AUTHORS: D E Jones, M M Elloso, P Scott

AFFILIATION: Department of Pathobiology, School of Veterinary Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
jonesdou at mail.med. upenn.edu

REFERENCE: Front Biosci 1998 Nov 3():D1171-80

The host-pathogen relationship is the focus of many different studies 
which use a variety of disease models and different pathogens. 
Immunological studies in the mouse using the intracellular parasite 
Leishmania have helped define several aspects of host-pathogen 
interactions. Resistance to Leishmania is dependent on the development 
of CD4+ Th1 cells which promote an effective cell mediated immune 
response. Production of the cytokine IFN-gamma during this immune 
response activates macrophages enabling them to kill the parasite and 
control the infection. In contrast, susceptibility to this parasite is 
characterized by a Th2 response which produces predominantly IL-4. This 
cytokine promotes high antibody titers directed towards the parasite but
 does not activate macrophages for parasite killing. This host response 
results in high parasite numbers and a progressive increase in lesion 
size. The mouse model of leishmaniasis has been extremely useful in 
gaining an understanding of the immunological factors important in 
determining T cell commitment into Th1 or Th2 populations during an in 
vivo immune response.




REQUEST: [ leishmania ]

(19 articles match this request. 9 articles matching other requests removed)



PMID: 15388442
 

TITLE: Antimicrobial Activity of Euplotin C, the Sesquiterpene Taxonomic Marker
from the Marine Ciliate Euplotes crassus.

AUTHORS: Dianella Savoia, Claudio Avanzini, Tiziano Allice, Emanuela Callone,
Graziano Guella, Fernando Dini

AFFILIATION: University of Turin, Department of Clinical and Biological
Sciences, S. Luigi Gonzaga Hospital, Orbassano (TO) 10043, Italy.
dianella.savoia at unito.it

REFERENCE: Antimicrob Agents Chemother 2004 Oct 48(10):3828-33

Strains of the marine ciliate protist Euplotes crassus produce exclusive
 terpenoids called euplotins that play an ecological role. Among these 
derivatives, euplotin C is the main of four secondary metabolites 
isolated from cultures of this protozoon and represents the 
sesquiterpene taxonomic marker from E. crassus. Because different 
terpenoid metabolites of plant origin showed a certain antimicrobial 
activity, we assessed the compound euplotin C, purified by high-pressure
 liquid chromatography and solubilized in two solubility enhancers, 
against the protozoa Leishmania major and Leishmani infantum, the fungus
 Candida albicans, and nine strains of gram-positive and gram-negative 
microorganisms. An activity of euplotin C against Leishmania 
promastigotes was demonstrated (50% lethal doses were 4.6 or 8.1 microg/
ml depending on the agent used to solubilize the compound), while the 
effect was less evident on Candida and nearly absent on bacteria. A 
nonsignificant cytotoxicity (50% lethal dose, >200 microg/ml) against 
the J774 cell line was observed. A leishmanicidal activity was also 
shown by the living, euplotin-producing cells of E. crassus cultured 
together with promastigotes; this activity increased with time from 10 
min to 6 h of incubation. This study provides an initial rationale for 
the evaluation of euplotin C and other similar natural products as 
alternative or possibly synergistic compounds for current antiprotozoon 
chemotherapeutics.




PMID: 15254033
 

TITLE: Endosomes, Glycosomes, and Glycosylphosphatidylinositol Catabolism in
Leishmania major.

AUTHORS: Zhifeng Zheng, Kimberly D Butler, Rodney K Tweten, Kojo Mensa-Wilmot

AFFILIATION: Department of Cellular Biology, the University of Georgia, Athens,
Georgia 30602.

REFERENCE: J Biol Chem 2004 Oct 279(40):42106-13

Glycosylphosphatidylinositols (GPIs) serve as membrane anchors of 
polysaccharides and proteins in the protozoan parasite Leishmania major
. Free GPIs that are not attached to macromolecules are present in L. 
major as intermediates of protein-GPI and polysaccharide-GPI synthesis 
or as terminal glycolipids. The importance of the intracellular location
 of GPIs in vivo for functions of the glycolipids is not appreciated. To
 examine the roles of intracellular free GPI pools for attachment to 
polypeptide, a GPI-specific phospholipase C (GPI-PLCp) from Trypanosoma 
brucei was used to probe trafficking of GPI pools inside L. major. The 
locations of GPIs were determined, and their catabolism by GPI-PLCp was 
analyzed with respect to the intracellular location of the enzyme. GPIs 
accumulated on the endo-lysosomal system, where GPI-PLCp was also 
detected. A peptide motif [CS][CS]-x(0,2)-G-x(1)-C-x(2,3)-S-x(3)-L 
formed part of an endosome targeting signal for GPI-PLCp. Mutations of 
the endosome targeting motif caused GPI-PLCp to associate with 
glycosomes (peroxisomes). Endosomal GPI-PLCp caused a deficiency of 
protein-GPI in L. major, whereas glycosomal GPI-PLCp failed to produce 
the GPI deficiency. We surmise that (i) endo-lysosomal GPIs are 
important for biogenesis of GPI-anchored proteins in L. major; (ii) 
sequestration of GPI-PLCp to glycosomes protects free protein-GPIs from 
cleavage by the phospholipase. In T. brucei, protein-GPIs are 
concentrated at the endoplasmic reticulum, separated from GPI-PLCp. 
These observations support a model in which glycosome sequestration of a
 catabolic GPI-PLCp preserves free protein-GPIs in vivo.




PMID: 15385463
 

TITLE: Immunization with Leishmania major Exogenous Antigens Protects
Susceptible BALB/c Mice against Challenge Infection with L. major.

AUTHORS: Willy K Tonui, J Santiago Mejia, Lisa Hochberg, M Lamine Mbow, Jeffrey
R Ryan, Adeline S T Chan, Samuel K Martin, Richard G Titus

AFFILIATION: Department of Microbiology Immunology and Pathology, CVMBS,
Colorado State University, 1619 Campus Delivery, Fort Collins, CO 80523-1619.
richard.titus at colostate.edu

REFERENCE: Infect Immun 2004 Oct 72(10):5654-61

The potential of Leishmania major culture-derived soluble exogenous 
antigens (SEAgs) to induce a protective response in susceptible BALB/c 
mice challenged with L. major promastigotes was investigated. Groups of 
BALB/c mice were immunized with L. major SEAgs alone, L. major SEAgs 
coadministered with either alum (aluminum hydroxide gel) or recombinant 
murine interleukin-12 (rmIL-12), L. major SEAgs coadministered with both
 alum and rmIL-12, and L. major SEAgs coadministered with Montanide ISA 
720. Importantly and surprisingly, the greatest and most consistent 
protection against challenge with L. major was seen in mice immunized 
with L. major SEAgs alone, in the absence of any adjuvant. Mice 
immunized with L. major SEAgs had significantly smaller lesions that at 
times contained more than 100-fold fewer parasites. When lymphoid cells 
from L. major SEAg-immunized mice were stimulated with leishmanial 
antigen in vitro, they proliferated and secreted a mixed profile of type
 1 and type 2 cytokines. Finally, analyses with Western blot analyses 
and antibodies against three surface-expressed and secreted molecules of
 L. major (lipophosphoglycan, gp46/M2/PSA-2, and gp63) revealed that two
 of these molecules are present in L. major SEAgs, lipophosphoglycan and
 the molecules that associate with it and gp46/M2/PSA-2.




PMID: 15388924
 

TITLE: Inhibition of Leishmania major pteridine reductase by
2,4,6-triaminoquinazoline: structure of the NADPH ternary complex.

AUTHORS: Karen McLuskey, Federica Gibellini, Paulo Carvalho, Mitchell A Avery,
William N Hunter

AFFILIATION: Division of Biological Chemistry and Molecular Microbiology, School
of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.

REFERENCE: Acta Crystallogr D Biol Crystallogr 2004 Oct 60(Pt 10):1780-5

The structure of Leishmania major pteridine reductase (PTR1) in complex 
with NADPH and the inhibitor 2,4,6-triaminoquinazoline (TAQ) has been 
solved in a new crystal form by molecular replacement and refined to 2.6
 A resolution. The inhibitor mimics a fragment, the pterin head group, 
of the archetypal antifolate drug methotrexate (MTX) and exploits 
similar chemical features to bind in the PTR1 active site. Despite being
 a much smaller molecule, TAQ displays a similar inhibition constant to 
that of MTX. PTR1 is a target for the development of improved therapies 
for infections caused by trypanosomatid parasites and this analysis 
provides information to assist the structure-based development of novel 
enzyme inhibitors.








PMID: 15362872
 

TITLE: Isomerase-independent chaperone function of cyclophilin ensures
aggregation prevention of adenosine kinase both in vitro and under in vivo
conditions.

AUTHORS: Anutosh Chakraborty, Banibrata Sen, Rupak Datta, Alok K Datta

AFFILIATION: Division of Infectious Diseases, Leishmania Group, Indian Institute
of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata-700 032, India.

REFERENCE: Biochemistry 2004 Sep 43(37):11862-72

Using inactive aggregates of adenosine kinase (AdK) from Leishmania 
donovani as the model substrate, we recently demonstrated that a 
cyclophilin (LdCyP) from the same source in an isomerase-independent 
fashion reactivated the enzyme in vitro by disaggregating its inactive 
oligomers [Chakraborty et al. (2002) J. Biol. Chem. 277, 47451-47460]. 
Besides disrupting preformed aggregates, LdCyP also prevents 
reaggregation of the newly formed active protein that is generated after
 productive refolding from its urea-denatured state. To investigate 
possible physiological implications of such phenomena, a unique 
expression system that simultaneously induces both AdK and LdCyP in 
naturally AdK-deficient Escherichia coli, was developed. Both in vitro 
and in vivo experiments revealed that oligomerization is an inherent 
property of this particular enzyme. In vivo protein cross-linking 
studies, activity determination analysis and Ado phosphorylation 
experiments carried out in cells coexpressing both the proteins 
unequivocally demonstrated that, similar to the phenomena observed in 
vitro, aggregates of the enzyme formed in vivo are able to interact with
 both LdCyP and its N-terminal truncated form (N(22-88)DEL LdCyP) in a 
crowded intracellular environment, resulting in aggregation prevention 
and reactivation of the enzyme. Our results indicate that the isomerase-
independent chaperone function of LdCyP, detected in vitro, participates
 in vivo as well to keep aggregation-prone proteins in a monomeric state
. Furthermore, analogous to yeast/bacterial two-hybrid systems, 
development of this simple coexpression system may help in the 
confirmation of interaction of two proteins under simulated in vivo 
conditions.




PMID: 15372110
 

TITLE: A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA-induced
IL-12 production and Th cell differentiation.

AUTHORS: Kenji Sugimoto, Mutsuhiro Ohata, Jun Miyoshi, Hiroyoshi Ishizaki,
Naotake Tsuboi, Akio Masuda, Yasunobu Yoshikai, Masaya Takamoto, Kazuo Sugane,
Seiichi Matsuo, Yasuhiro Shimada, Tetsuya Matsuguchi

AFFILIATION: Division of Host Defense, Center for Neural Disease and Cancer,
Nagoya University Graduate School of Medicine, Japan.

REFERENCE: J Clin Invest 2004 Sep 114(6):857-66

A serine/threonine protein kinase, Cot/Tpl2, is indispensable for 
extracellular signal-regulated kinase (ERK) activation and production of
 TNF-alpha and PGE2 in LPS-stimulated macrophages. We show here that Cot
/Tpl2 is also activated by other Toll-like receptor (TLR) ligands. 
Bacterial DNA rich in the dinucleotide CG (CpG-DNA), unlike LPS or 
synthetic lipopeptide, activated ERK in a Cot/Tpl2-independent manner. 
Peritoneal macrophages and bone marrow-derived DCs from Cot/Tpl2-/- mice
 produced significantly more IL-12 in response to CpG-DNA than those 
from WT mice. Enhanced IL-12 production in Cot/Tpl2-/- macrophages is, 
at least partly, regulated at the transcriptional level, and the 
elevated IL-12 mRNA level in Cot/Tpl2-/- macrophages is accompanied by 
decreased amounts of IL-12 repressors, such as c-musculoaponeurotic 
fibrosarcoma (c-Maf) and GATA sequence in the IL-12 promoter-binding 
protein (GA-12-binding protein; GAP-12) in the nucleus. Consistently, 
Cot/Tpl2-/- mice showed Th1-skewed antigen-specific immune responses 
upon OVA immunization and Leishmania major infection in vivo. These 
results indicate that Cot/Tpl2 is an important negative regulator of Th1
-type adaptive immunity, that it achieves this regulation by inhibiting 
IL-12 production from accessory cells, and that it might be a potential 
target molecule in CpG-DNA-guided vaccination.




PMID: 15361310
 

TITLE: Activity of dihydroartemisinin against Leishmania donovani both in vitro
and vivo.

AUTHORS: Ying Ma, Dian-mei Lu, Xiao-jun Lu, Lin Liao, Xiao-su Hu

AFFILIATION: Department of Parasitology, School of Preclinical and Forensic
Medicine, Sichuan University, Chengdu 610041, China.

REFERENCE: Chin Med J (Engl) 2004 Aug 117(8):1271-3




PMID: 15379431
 

TITLE: Canine visceral leishmaniosis in Anastácio, Mato Grosso do Sul state,
Brazil.

AUTHORS: V M C L Cortada, M E C Doval, M A A Souza Lima, E T Oshiro, C R V
Meneses, A L Abreu-Silva, E Cupolilo, C S F Souza, F O Cardoso, T Zaverucha do
Valle, R P Brazil, K S Calabrese, S C Gonçalves da Costa

AFFILIATION: Departamento de Patologia, Laboratório de Parasitologia Humana,
Universidade Federal de Mato Grosso do Sul, Brazil.

REFERENCE: Vet Res Commun 2004 Jul 28(5):365-74

Canine visceral leishmaniosis (CVL) may be an important factor preceding
 human outbreaks of the disease. We report that the prevalence of canine
 visceral leishmaniosis infection has been increasing in recent years in
 Anastácio town, located in the central western region of Brazil. 
Serological investigations showed that 75.3% of dogs presented antibody 
titres ranging from 1/40 to 1/160 in the indirect immunofluorescence 
antibody test (IFAT). Bone marrow and lymph node aspirates provided 
positive cultures and furnished parasites for enzymological and 
serological typing in 42.5% and 41.1% of the cases, respectively. All 
the strains were typed as Leishmania (L.) chagasi. This is primarily a 
canine disease that spills over into the human population as a zoonosis
. The study showed the epidemiological features of the infection in a 
region in which the problem of visceral leishmaniosis has been 
underestimated.




PMID: 15125525
 

TITLE: A simple micro-assay method for estimating blood meal size of the sand
fly, Phlebotomus langeroni (Diptera: Psychodidae).

AUTHORS: S Daba, As Daba, M G Shehata, B M El Sawaf

AFFILIATION: Research and Training Center on Vectors of Diseases, Ain Shams
University, Cairo 11566, Egypt.

REFERENCE: J Egypt Soc Parasitol 2004 Apr 34(1):173-82

The accurate measurement of blood meal size in Phlebotomus langeroni, 
the potential vector of infantile visceral leishmaniasis in Egypt, is 
important to determine the number of parasites taken in fully engorged 
insects. A simple protein content micro-assay is introduced for that 
purpose. The accuracy of this method was confirmed by hemoglobin 
estimation method. Laboratory bred P. langeroni were fed artificially on
 defibrinated human blood and the fully engorged flies were carefully 
dissected on ice, within 1-10 min after feeding, since the time of 
dissection is critical. Serial concentrations of the defibrinated human 
blood were required as standards. Results show that the full blood meal 
taken by P. langeroni ranged from 0.76-0.94 mm3 of blood with a mean 
volume of 0.85 +/- 0.02 mm3 and from 0.71- 0.99 mm3 of blood with a mean
 volume of 0.83 +/- 0.02 mm3 as measured by protein content and 
hemoglobin estimation methods respectively. The data showed that there 
is no significant difference (P=0.27) between the two methods in 
estimating the blood meal size of P. langeroni. In addition, protein 
content micro-assay had the advantages of being accurate, rapid, 
sensitive and reliable.




PMID: 15388992
 

TITLE: Experimental Leishmania major Infection Suppresses HIV-1 DNA Vaccine
Induced Cellular Immune Response.

AUTHORS: Tara M Robinson, Robin Nelson, David Artis, Phillip Scott, Jean D
Boyer

AFFILIATION: Department of Pathology and Laboratory Medicine, University of
Pennsylvania, Philadelphia, Pa., USA.

REFERENCE: Cells Tissues Organs 2004  177(3):185-8

The AIDS epidemic in the developing world represents a major global 
crisis and an effective vaccine is imperative. However, many parasites 
are common in developing countries and can result in a state of chronic 
immune activation that is polarized towards a Th2 profile and which can 
potentially impair responses to vaccines or other infectious challenges
. In this study we demonstrate that experimental Leishmania major 
infection of BALB/c mice inhibits responses to a DNA-based HIV-1 gag 
vaccine. L. major infection in BALB/c results in a polarized Th2 immune 
response. In this study naïve BALB/c mice immunized with the HIV-1 gag 
DNA vaccine mounted a cellular immune response against the vaccine 
antigen, HIV-1 gag. CD8+ T lymphocytes were able to respond in vitro to 
HIV-1 gag stimulation and secrete interferon (IFN)-gamma. However, L. 
major-infected, vaccinated BALB/c mice had a significantly reduced 
number of IFN-gamma-producing CD8+ T cells following in vitro 
stimulation with gag antigen. These data suggest that parasitic 
infection, which results in a Th2 profile, reduces the efficacy of DNA 
vaccines that are designed to induce antiviral CD8+ T cell responses. 
Copyright 2004 S. Karger AG, Basel




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