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REQUEST: [ leishmaniasis ]

(16 articles match this request)



PMID: 15451003
 

TITLE: Design, synthesis and in vitro evaluation of novel water-soluble prodrugs
of buparvaquone.

AUTHORS: Antti Mäntylä, Jarkko Rautio, Tapio Nevalainen, Pekka Keski-Rahkonen,
Jouko Vepsälainen, Tomi Järvinen

AFFILIATION: Department of Pharmaceutical Chemistry, University of Kuopio, P.O.
Box 1627, FIN-70211 Kuopio, Finland.

REFERENCE: Eur J Pharm Sci 2004 Oct 23(2):151-8

Novel water-soluble phosphate prodrugs (2b-5b) of buparvaquone-oxime (1a
) and buparvaquone-O-methyloxime (1b) were synthesized and evaluated in 
vitro as potential oral prodrugs against leishmaniasis. Buparvaquone-
oxime (1a), and most probably also buparvaquone-O-methyloxime (1b), 
released the parent buparvaquone via a cytochrome P450-catalysed 
reaction. The prodrugs 2b-5b showed significantly higher aqueous 
solubilities (>4mg/ml) than buparvaquone (</=0.03microg/ml) over a 
pH range of 3.0-7.4. The prodrugs 2b, 3b and 5b rapidly released (t(1/2
) = 7min) the corresponding oximes of buparvaquone (1a and 1b), and 
prodrug 4b at a moderate rate (t(1/2) = 22.5min) in alkaline phosphatase
 solution in vitro. Prodrug 3b was the most chemically stable in the 
aqueous solutions over a pH range of 3.0-7.4 (t(1/2) > 8 days). Although
 buparvaquone-oxime (1a) has been shown to undergo a cytochrome P450-
catalysed oxidation in liver microsomes to the parent buparvaquone and 
behave as a novel bioreversible prodrug, its usefulness is limited in 
oral drug delivery due to its poor aqueous solubility, like buparvaquone
 itself. Further phosphorylation of an oxime form of buparvaquone 
significantly increased water solubility, and this novel approach is 
therefore useful to improve physicochemical properties of drugs 
containing a ketone functional group.








PMID: 15273118
 

TITLE: Inhibitors of Leishmania mexicana CRK3 cyclin-dependent kinase: chemical
library screen and antileishmanial activity.

AUTHORS: Karen M Grant, Morag H Dunion, Vanessa Yardley, Alexios-Leandros
Skaltsounis, Doris Marko, Gerhard Eisenbrand, Simon L Croft, Laurent Meijer,
Jeremy C Mottram

AFFILIATION: Wellcome Centre for Molecular Parasitology, University of Glasgow,
Glasgow, United Kingdom. k.grant at vet.gla.ac.uk

REFERENCE: Antimicrob Agents Chemother 2004 Aug 48(8):3033-42

The CRK3 cyclin-dependent kinase of Leishmania has been shown by genetic
 manipulation of the parasite to be essential for proliferation. We 
present data which demonstrate that chemical inhibition of CRK3 impairs 
the parasite's viability within macrophages, thus further validating 
CRK3 as a potential drug target. A microtiter plate-based histone H1 
kinase assay was developed to screen CRK3 against a chemical library 
enriched for protein kinase inhibitors. Twenty-seven potent CRK3 
inhibitors were discovered and screened against Leishmania donovani 
amastigotes in vitro. Sixteen of the CRK3 inhibitors displayed 
antileishmanial activity, with a 50% effective dose (ED50) of less than 
10 microM. These compounds fell into four chemical classes: the 2,6,9-
trisubstituted purines, including the C-2-alkynylated purines; the 
indirubins; the paullones; and derivatives of the nonspecific kinase 
inhibitor staurosporine. The paullones and staurosporine derivatives 
were toxic to macrophages. The 2,6,9-trisubstituted purines inhibited 
CRK3 in vitro, with 50% inhibitory concentrations ranging from high 
nanomolar to low micromolar concentrations. The most potent inhibitors 
of CRK3 (compounds 98/516 and 97/344) belonged to the indirubin class; 
the 50% inhibitory concentrations for these inhibitors were 16 and 47 nM
, respectively, and the ED50s for these inhibitors were 5.8 and 7.6 
microM, respectively. In culture, the indirubins caused growth arrest, a
 change in DNA content, and aberrant cell types, all consistent with the
 intracellular inhibition of a cyclin-dependent kinase and disruption of
 cell cycle control. Thus, use of chemical inhibitors supports genetic 
studies to confirm CRK3 as a validated drug target in Leishmania and 
provides pharmacophores for further drug development.




PMID: 15273114
 

TITLE: Possible mechanism of miltefosine-mediated death of Leishmania donovani.

AUTHORS: Navin K Verma, Chinmoy S Dey

AFFILIATION: Department of Biotechnology, National Institute of Pharmaceutical
Education and Research, Punjab, India.

REFERENCE: Antimicrob Agents Chemother 2004 Aug 48(8):3010-5

Miltefosine causes leishmanial death, but the possible mechanism(s) of 
action is not known. The mode of action of miltefosine was investigated 
in vitro in Leishmania donovani promastigotes as well as in extra- and 
intracellular amastigotes. Here, we demonstrate that miltefosine induces
 apoptosis-like death in L. donovani based on observed phenomena such as
 nuclear DNA condensation, DNA fragmentation with accompanying ladder 
formation, and in situ labeling of DNA fragments by the terminal 
deoxyribonucleotidyltransferase-mediated dUTP-biotin nick end labeling 
method. Understanding of miltefosine-mediated death will facilitate the 
design of new therapeutic strategies against Leishmania parasites.




PMID: 15454691
 

TITLE: Identification of 9- O -acetylated sialoglycans on peripheral blood
mononuclear cells in Indian Visceral Leishmaniasis.

AUTHORS: Sumi Bandyopadhyay, Mitali Chatterjee, Shyam Sundar, Chitra Mandal

AFFILIATION: Immunobiology Division, Indian Institute of Chemical Biology, 4
Raja S.C. Mullick Road, Kolkata 700 032.

REFERENCE: Glycoconj J 2004  20(9):531-6

Although the existence of O -acetylated sialic acids is well known, it 
is only in recent years that steady refinement of analytical techniques 
have enabled detailed mapping of their structural diversity [1]. 
Fluorimetric analysis of peripheral blood mononuclear cells (PBMC) of 
patients with Visceral Leishmaniasis (VL) showed six fold increase in 
the percentage of surface 9- O -acetylated sialoglycoconjugates (9- O -
AcSGs) as compared to normal human donors. Using Achatinin-H, a 9- O -
acetyl sialic acid- binding lectin, an enhanced presence of 9- O -AcSGs 
in an alpha 2 --> 6 linkage was demonstrated by flow cytometry; 
abolition of its binding by pretreatment with a recombinant 9- O -
acetylesterase corroborated the presence of this glycotope. Western 
blotting of PBMC from VL patients indicated the presence of five O -
acetylated sialoglycans corresponding to 144, 65, 56, 36 and 19 kDa as 
compared to 144 and 36 kDa in normal individuals. Taken together our 
data indicates that during active disease, there is an overexpression of
 9- O -AcSGs on the surface of PBMC of VL patients, thus opening up new 
research avenues wherein the expression of this biomarker could be 
exploited to monitor the clinical status of VL patients. Published in 
2004.




PMID: 15455792
 

TITLE: [Acute renal failure complicating a visceral leishmaniasis]

AUTHORS: V Chaigne, Y Knefati, R Lafarge, J Bronner, B Mc Gregor, D Fouque, J C
Sabatier

AFFILIATION: Service de néphrologie, Centre hospitalier E.Herriot, Lyon.

REFERENCE: Nephrologie 2004  25(5):179-83

Renal involvement is an unusual complication of human visceral 
leishmaniasis (VL). The kidney lesions are characterized more by 
interstitial damage than glomerular or vascular damage. This case 
represents a 20 years-old man admitted with pancytopenia, purpura, acute
 renal failure, and nephrotic syndrome associated with heavy proteinuria
. The diagnosis of VL was made on bone marrow smear cytology where 
Leishmania amastigotes were found. The renal biopsy revealed a segmental
 necrotising glomerulonephritis with 70% crescents. Treatment with 
liposomal amphotericine B alone has been ineffective on the course of 
renal failure, however, partial recovery was obtained after the 
administration of high dose corticosteroids. We present the various 
clinical, biological, and histological aspects of this case, from the 
south of France. It gave us the opportunity to discuss these unusual 
manifestations of immunomediated necrotising skin and renal lesions.




********************************************************************************************************************

 The following references are revised files and are brought to you in accordance
to license agreement with the NLM.

********************************************************************************************************************


PMID: 12916382
 

TITLE: Massive hepatomegaly due to visceral leishmaniasis.

AUTHORS: Halima Dawood, Christopher Jack, Umesh G Lalloo, Melanie-Anne John,
Vincent Naicker

REFERENCE: S Afr Med J 2003 Jun 93(6):441-2




PMID: 12117930
 

TITLE: Immunization with a polyprotein vaccine consisting of the T-Cell antigens
thiol-specific antioxidant, Leishmania major stress-inducible protein 1, and
Leishmania elongation initiation factor protects against leishmaniasis.

AUTHORS: Rhea N Coler, Yasir A W Skeiky, Karen Bernards, Kay Greeson, Darrick
Carter, Charisa D Cornellison, Farrokh Modabber, Antonio Campos-Neto, Steven G
Reed

AFFILIATION: Infectious Disease Research Institute, Seattle, Washington 98104,
USA. coler at idri.org

REFERENCE: Infect Immun 2002 Aug 70(8):4215-25

Development of an effective vaccine against Leishmania infection is a 
priority of tropical disease research. We have recently demonstrated 
protection against Leishmania major in the murine and nonhuman primate 
models with individual or combinations of purified leishmanial 
recombinant antigens delivered as plasmid DNA constructs or formulated 
with recombinant interleukin-12 (IL-12) as adjuvant. In the present 
study, we immunized BALB/c mice with a recombinant polyprotein 
comprising a tandem fusion of the leishmanial antigens thiol-specific 
antioxidant, L. major stress-inducible protein 1 (LmSTI1), and 
Leishmania elongation initiation factor (LeIF) delivered with adjuvants 
suitable for human use. Aspects of the safety, immunogenicity, and 
vaccine efficacy of formulations with each individual component, as well
 as the polyprotein referred to as Leish-111f, were assessed by using 
the L. major challenge model with BALB/c mice. No adverse reactions were
 observed when three subcutaneous injections of the Leish-111f 
polyprotein formulated with either MPL-squalene (SE) or Ribi 529-SE were
 given to BALB/c mice. A predominant Th1 immune response characterized 
by in vitro lymphocyte proliferation, gamma interferon production, and 
immunoglobulin G2A antibodies was observed with little, if any, IL-4. 
Moreover, Leish-111f formulated with MPL-SE conferred immunity to 
leishmaniasis for at least 3 months. These data demonstrate success at 
designing and developing a prophylactic leishmaniasis vaccine that 
proved effective in a preclinical model using multiple leishmanial 
antigens produced as a single protein delivered with a powerful Th1 
adjuvant suitable for human use.








PMID: 12010969
 

TITLE: Vaccination with plasmid DNA encoding TSA/LmSTI1 leishmanial fusion
proteins confers protection against Leishmania major infection in susceptible
BALB/c mice.

AUTHORS: A Campos-Neto, J R Webb, K Greeson, R N Coler, Y A W Skeiky, S G Reed

AFFILIATION: Infectious Disease Research Institute. Corixa Corporation, Seattle,
Washington 98104, USA. acampos at idri.org

REFERENCE: Infect Immun 2002 Jun 70(6):2828-36

We have recently shown that a cocktail containing two leishmanial 
recombinant antigens (LmSTI1 and TSA) and interleukin-12 (IL-12) as an 
adjuvant induces solid protection in both a murine and a nonhuman 
primate model of cutaneous leishmaniasis. However, because IL-12 is 
difficult to prepare, is expensive, and does not have the stability 
required for a vaccine product, we have investigated the possibility of 
using DNA as an alternative means of inducing protective immunity. Here
, we present evidence that the antigens TSA and LmSTI1 delivered in a 
plasmid DNA format either as single genes or in a tandem digene 
construct induce equally solid protection against Leishmania major 
infection in susceptible BALB/c mice. Immunization of mice with either 
TSA DNA or LmSTI1 DNA induced specific CD4(+)-T-cell responses of the 
Th1 phenotype without a requirement for specific adjuvant. CD8 responses
, as measured by cytotoxic-T-lymphocyte activity, were generated after 
immunization with TSA DNA but not LmSTI1 DNA. Interestingly, vaccination
 of mice with TSA DNA consistently induced protection to a much greater 
extent than LmSTI1 DNA, thus supporting the notion that CD8 responses 
might be an important accessory arm of the immune response for acquired 
resistance against leishmaniasis. Moreover, the protection induced by 
DNA immunization was specific for infection with Leishmania, i.e., the 
immunization had no effect on the course of infection of the mice 
challenged with an unrelated intracellular pathogen such as 
Mycobacterium tuberculosis. Conversely, immunization of BALB/c mice with
 a plasmid DNA that is protective against challenge with M. tuberculosis
 had no effect on the course of infection of these mice with L. major. 
Together, these results indicate that the protection observed with the 
leishmanial DNA is mediated by acquired specific immune response rather 
than by the activation of nonspecific innate immune mechanisms. In 
addition, a plasmid DNA containing a fusion construct of the two genes 
was also tested. Similarly to the plasmids encoding individual proteins
, the fusion construct induced both specific immune responses to the 
individual antigens and protection against challenge with L. major. 
These results confirm previous observations about the possibility of DNA
 immunization against leishmaniasis and lend support to the idea of 
using a single polygenic plasmid DNA construct to achieve polyspecific 
immune responses to several distinct parasite antigens.




PMID: 2648612
 

TITLE: Leishmaniasis in South West Africa/Namibia to date.

AUTHORS: S S Grové

AFFILIATION: Regional Laboratory Services, Hospital and Health Services Branch,
Cape Provincial Administration, Cape Town.

REFERENCE: S Afr Med J 1989 Mar 75(6):290-2

A total of 34 patients with cutaneous leishmaniasis (CL) have been 
diagnosed in South West Africa/Namibia since 1970. Visceral 
leishmaniasis has not occurred. So far a sandfly Phlebotomus rossi has 
emerged as a possible vector of the disease in man. Several aspects of 
vector incrimination and bionomics still need clarification. Further 
carefully planned and directed field studies are required in an attempt 
to identify the reservoir host for human CL.




PMID: 550447
 

TITLE: Cutaneous leishmaniasis in Southern Africa.

AUTHORS: J A Campbell, W Gordon, M Emms

REFERENCE: S Afr Med J 1979 Dec 56(26):1113




PMID: 694605
 

TITLE: The clinical and histological features of South West African cutaneous
leishmaniasis.

AUTHORS: S S Grové

REFERENCE: S Afr Med J 1978 May 53(18):712-5

The clinical and histological features of 18 cases of dermal 
leishmaniasis encountered in South West Africa are described and 
discussed. The anatomical distribution of the leishmanial lesions 
differs from that encountered elsewhere in Africa, but the 
histopathological changes follow a pattern similar to that of Oriental 
sore in other parts of the world.




PMID: 694606
 

TITLE: Cutaneous leishmaniasis in Southern Africa. A case report.

AUTHORS: G S Rutherfoord, C J Uys

REFERENCE: S Afr Med J 1978 May 53(18):716-8

The microscopical findings in a case of cutaneous leishmaniasis from 
South West Africa are presented in order to highlight the pathology of 
this disease and facilitate its recognition, should unsuspected cases 
occur in the Republic of South Africa. In addition, the ultrastructural 
findings confirm the presence of typical Leishmania which occur in the 
cytoplasm of macrophages where they are undergoing destruction. This 
adds a further dimension to the characterization of this disease in 
southern Africa.




PMID: 4826759
 

TITLE: Cutaneous leishmaniasis in an Ovambo.

AUTHORS: S S Grové, J H Van Dyk

REFERENCE: S Afr Med J 1974 Mar 47(12):516-7








PMID: 4687016
 

TITLE: Cutaneous leishmaniasis.

AUTHORS: E Holland

REFERENCE: S Afr Med J 1973 Jan 47(3):83




PMID: 5553608
 

TITLE: Leishmaniasis in South West Africa: preliminary notes on host reservoir
and vector studies.

AUTHORS: S S Grové, R Downes, E Zielke

REFERENCE: S Afr Med J 1971 Mar 45(11):293-4




PMID: 5438941
 

TITLE: Cutaneous leishmaniasis in South West Africa.

AUTHORS: S S Grové

REFERENCE: S Afr Med J 1970 Feb 44(8):206-7




REQUEST: [ leishmania ]

(15 articles match this request. 5 articles matching other requests removed)



PMID: 15450848
 

TITLE: Calorimetric determination of thermodynamic parameters of 2'-dUMP binding
to Leishmania major dUTPase.

AUTHORS: Irene Domínguez-Pérez, Ramiro Téllez-Sanz, Isabel Leal, Luis M
Ruíz-Pérez, Dolores González-Pacanowska, Luis García-Fuentes

AFFILIATION: Dpto. de Química Física, Bioquímica y Q. Inorgánica, Facultad
de Ciencias Experimentales, Universidad de Almería, La Cañada de San Urbano,
04120 Almería, Spain.

REFERENCE: Biochim Biophys Acta 2004 Oct 1702(1):33-40

We have investigated the binding of 2'-deoxyuridine 5'-monophosphate (2
'-dUMP) to Leishmania major deoxyuridine 5'-triphosphate nucleotide 
hydrolase (dUTPase) by isothermal titration microcalorimetry under 
different experimental conditions. Binding to dimeric L. major dUTPase 
is a non-cooperative process, with a stoichiometry of 1 molecule of 2'-
dUMP per subunit. The utilization of buffers with different ionization 
enthalpies has allowed us to conclude that the formation of the 2'-dUMP-
dUTPase complex, at pH 7.5 and 30 degrees C, is accompanied by the 
uptake of 0.33+/-0.05 protons per dUTPase subunit from the buffer media
. Moreover, 2'-dUMP shows a moderate affinity for the enzyme, and 
binding is enthalpically driven across the temperature range studied. 
Besides, whereas DeltaG degrees remains practically invariant as a 
function of temperature, both DeltaH and DeltaS degrees decrease with 
increasing temperature. The T(S) and T(H) were 23.4 and 13.6 degrees C, 
respectively. The temperature dependence of the enthalpy change yields a
 heat capacity change of DeltaC(p) degrees =-618.1+/-126.4 cal.mol(-1).K
(-1), a value low enough to discard major conformational changes, in 
agreement with the fitting model. An interpretation of this value in 
terms of solvent-accessible surface areas is provided.




PMID: 15329361
 

TITLE: Effect of the lysophospholipid analogues edelfosine, ilmofosine and
miltefosine against Leishmania amazonensis.

AUTHORS: Ricardo M Santa-Rita, Andréa Henriques-Pons, Helene S Barbosa, Solange
L De Castro

AFFILIATION: Dept. de Ultra-estrutura e Biologia Celular, Instituto Oswaldo
Cruz, Fundação Oswaldo Cruz, 21045-900, Rio de Janeiro-RJ, Brazil.

REFERENCE: J Antimicrob Chemother 2004 Oct 54(4):704-10

OBJECTIVES: Analysis of the effect of edelfosine, ilmofosine and 
miltefosine on Leishmania amazonensis and of potential targets of these 
lysophospholipid analogues. METHODS: Quantification and ultrastructural 
analysis of the effect of lysophospholipid analogues on promastigote 
forms and on infected peritoneal macrophages, and flow cytometry 
analysis of treated promastigotes labelled with propidium iodide and 
rhodamine 123 (Rh123). RESULTS: The lysophospholipid analogues presented
 potent antiproliferative activity with IC(50)/3 days of 1.9-3.4 microM 
for promastigotes and 4.2-9.0 microM for intracellular amastigotes. 
Treatment with these analogues in Schneider medium for 1 day led to a 
dose-dependent decrease in Rh123 fluorescence, an effect more 
accentuated in edelfosine-treated parasites, suggesting interference 
with the potential of the mitochondrial membrane. In both forms of L. 
amazonensis, edelfosine induced extensive mitochondrial damage, 
multinucleation and, in promastigotes, also led to plasma membrane 
alterations, formation of autophagic structures and membranous 
arrangements inside the flagellar pocket. CONCLUSIONS: The 
alkylglycerophosphocholines edelfosine and ilmofosine were more active 
than the alkylphosphocholine miltefosine against promastigotes and 
intracellular amastigotes of L. amazonensis, and ultrastructural and 
flow cytometry data indicate the mitochondrion as a target of edelfosine.




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, Colorado State
University, Fort Collins, Colorado 80523-1619, USA.

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: 15448686
 

TITLE: Central memory T cells mediate long-term immunity to Leishmania major in
the absence of persistent parasites.

AUTHORS: Colby Zaph, Jude Uzonna, Stephen M Beverley, Phillip Scott

AFFILIATION: [1] Department of Pathobiology, University of Pennsylvania, 3800
Spruce Street, Philadelphia, Pennsylvania 19104, USA. [2] These authors
contributed equally to this work.

REFERENCE: Nat Med 2004 Oct 10(10):1104-10

Infection with Leishmania major induces a protective immune response and
 long-term resistance to reinfection, which is thought to depend upon 
persistent parasites. Here we demonstrate that although effector CD4(+) 
T cells are lost in the absence of parasites, central memory CD4(+) T 
cells are maintained. Upon secondary infection, these central memory T 
cells become tissue-homing effector T cells and mediate protection. Thus
, immunity to L. major is mediated by at least two distinct populations 
of CD4(+) T cells: short-lived pathogen-dependent effector cells and 
long-lived pathogen-independent central memory cells. These data suggest
 that central memory T cells should be the targets for nonlive vaccines 
against infectious diseases requiring cell-mediated immunity.




PMID: 15304317
 

TITLE: Multiple terminal uridylyltransferases of trypanosomes.

AUTHORS: Ruslan Aphasizhev, Inna Aphasizheva, Larry Simpson

AFFILIATION: Department of Microbiology, Immunology, and Molecular Genetics,
University of California, Los Angeles, CA 90095, USA. ruslan at uci.edu

REFERENCE: FEBS Lett 2004 Aug 572(1-3):15-8

The transferase activities that add uridylyl residues to RNA have been 
reported in several unicellular and metazoan organisms. Thus far, the 
two terminal uridylyltransferases (TUTases) involved in uridine 
insertion/deletion mRNA editing in mitochondria of trypanosomes were the
 only known enzymes with confirmed UTP specificity. Here, we demonstrate
 that protein sequences of editing TUTases may be used to predict novel 
UTP-specific enzymes by data mining. The highest-scoring open reading 
frame from Trypanosoma brucei was expressed and recombinant protein 
purified. This enzyme catalyzes a processive UMP incorporation and is 
not localized to the mitochondria suggesting a non-editing biological 
function.




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 19104, 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.




********************************************************************************************************************

 The following references are revised files and are brought to you in accordance
to license agreement with the NLM.

********************************************************************************************************************


PMID: 12529367
 

TITLE: Role of peroxidoxins in Leishmania chagasi survival. Evidence of an
enzymatic defense against nitrosative stress.

AUTHORS: Stephen D Barr, Lashitew Gedamu

AFFILIATION: Department of Biological Sciences, University of Calgary, Alberta
T2N 1N4, Canada.

REFERENCE: J Biol Chem 2003 Mar 278(12):10816-23

The mechanisms by which Leishmania parasites survive exposure to highly 
reactive oxygen (ROS) and nitrogen (RNS) species within phagosomes of 
macrophages are not well known. Recently it has been shown that RNS 
alone is sufficient and necessary to control Leishmania donovani 
infection in mice (Murray, H. W., and Nathan, C. F. (1999) J. Exp. Med. 
189, 741-746). No enzymatic defense against RNS has been discovered in 
Leishmania to date. We have previously isolated two peroxidoxins (LcPxn1
 and LcPxn2) from Leishmania chagasi and showed that recombinant LcPxn1 
protein was capable of detoxifying hydrogen peroxide, hydroperoxide, and
 hydroxyl radicals (Barr, S. D., and Gedamu, L. (2001) J. Biol. Chem. 
276, 34279-34287). In further characterizing the physiological role of 
peroxidoxins in Leishmania survival, we show here that recombinant 
LcPxn1 protein can detoxify RNS in addition to ROS, whereas recombinant 
LcPxn2 protein can only detoxify hydrogen peroxide. LcPxn1 and LcPxn2 
are localized to the cytoplasm, and overexpression of LcPxn1 in L. 
chagasi parasites enhanced survival when exposed to exogenous ROS and 
RNS and enhanced survival within U937 macrophage cells. Site-directed 
mutagenesis studies revealed that the conserved Cys-52 residue is 
essential for detoxifying hydrogen peroxide, t-butyl hydroperoxide, and 
hydroxyl radicals, whereas the conserved Cys-173 residue is essential 
for detoxifying t-butyl hydroperoxide and peroxynitrite. This is the 
first report of an enzymatic defense against RNS in Leishmania.




PMID: 12446214
 

TITLE: Specificity and kinetics of a mitochondrial peroxiredoxin of Leishmania
infantum.

AUTHORS: Helena Castro, Heike Budde, Leopold Flohé, Birgit Hofmann, Heinrich
Lünsdorf, Joseph Wissing, Ana M Tomás

AFFILIATION: Institute for Molecular and Cell Biology, Porto, Portugal.

REFERENCE: Free Radic Biol Med 2002 Dec 33(11):1563-74

In Kinetoplastida, comprising the medically important parasites 
Trypanosoma brucei, T. cruzi, and Leishmania species, 2-Cys 
peroxiredoxins described to date have been shown to catalyze reduction 
of peroxides by the specific thiol trypanothione using tryparedoxin, a 
thioredoxin-related protein, as an immediate electron donor. Here we 
show that a mitochondrial peroxiredoxin from L. infantum (LimTXNPx) is 
also a tryparedoxin peroxidase. In an heterologous system constituted by
 nicotinamide adenine dinucleotide phosphate (NADPH), T. cruzi 
trypanothione reductase, trypanothione and Crithidia fasciculata 
tryparedoxin (CfTXN1 and CfTXN2), the recombinant enzyme purified from 
Escherichia coli as an N-terminally His-tagged protein preferentially 
reduces H(2)O(2) and tert-butyl hydroperoxide and less actively cumene 
hydroperoxide. Linoleic acid hydroperoxide and phosphatidyl choline 
hydroperoxide are poor substrates in the sense that they are reduced 
weakly and inhibit the enzyme in a concentration- and time-dependent way
. Kinetic parameters deduced for LimTXNPx are a k(cat) of 37.0 s(-1) and
 K(m) values of 31.9 and 9.1 microM for CfTXN2 and tert-butyl 
hydroperoxide, respectively. Kinetic analysis indicates that LimTXNPx 
does not follow the classic ping-pong mechanism described for other 
TXNPx (Phi(1,2) = 0.8 s x microM(2)). Although the molecular mechanism 
underlying this finding is unknown, we propose that cooperativity 
between the redox centers of subunits may explain the unusual kinetic 
behavior observed. This hypothesis is corroborated by high-resolution 
electron microscopy and gel chromatography that reveal the native enzyme
 to preferentially exist as a homodecameric ring structure composed of 
five dimers.




PMID: 12446213
 

TITLE: Complementary antioxidant defense by cytoplasmic and mitochondrial
peroxiredoxins in Leishmania infantum.

AUTHORS: Helena Castro, Carla Sousa, Marta Santos, Anabela Cordeiro-da-Silva,
Leopold Flohé, Ana M Tomás

AFFILIATION: Institute for Molecular and Cell Biology, Porto, Portugal.

REFERENCE: Free Radic Biol Med 2002 Dec 33(11):1552-62

In Kinetoplastida 2-Cys peroxiredoxins are the ultimate members of 
unique enzymatic cascades for detoxification of peroxides, which are 
dependent on trypanothione, a small thiol specific to these organisms. 
Here we report on two distinct Leishmania infantum peroxiredoxins, 
LicTXNPx and LimTXNPx, that may be involved in such a pathway. LicTXNPx
, found in the cytoplasm, is a typical 2-Cys peroxiredoxin encoded by 
LicTXNPx, a member of a multicopy gene family. LimTXNPx, encoded by a 
single copy gene, LimTXNPx, is confined to the mitochondrion and is 
unusual in possessing an Ile-Pro-Cys motif in the distal redox center, 
replacing the common peroxiredoxin Val-Cys-Pro sequence, apart from an N
-terminal mitochondrial leader sequence. Based on sequence and 
subcellular localization, the peroxiredoxins of Kinetoplastida can be 
separated in two distinct subfamilies. As an approach to investigate the
 function of both peroxiredoxins in the cell, L. infantum promastigotes 
overexpressing LicTXNPx and LimTXNPx were assayed for their resistance 
to H(2)O(2) and tert-butyl hydroperoxide. The results show evidence that
 both enzymes are active as peroxidases in vivo and that they have 
complementary roles in parasite protection against oxidative stress.




PMID: 11438539
 

TITLE: Cloning and characterization of three differentially expressed
peroxidoxin genes from Leishmania chagasi. Evidence for an enzymatic
detoxification of hydroxyl radicals.

AUTHORS: S D Barr, L Gedamu

AFFILIATION: Department of Biological Sciences, University of Calgary, Calgary,
Alberta T2N 1N4, Canada.

REFERENCE: J Biol Chem 2001 Sep 276(36):34279-87

Antioxidants have been implicated in protecting cells from oxygen 
radicals produced as a result of aerobic metabolism and in response to 
foreign pathogens by phagocytic cells. The mechanisms allowing pathogens
 to withstand the toxic prooxidant environment within the phagolysosome 
are poorly understood. We have cloned and characterized three 
antioxidant genes belonging to the 2-Cys family of peroxidoxins from 
Leishmania chagasi that may prove to provide these parasites with an 
enhanced defense mechanism against toxic oxidants. The 5'-untranslated 
regions and coding regions of each gene are highly conserved, whereas 
the 3'-untranslated regions have diverged significantly. L. chagasi 
peroxidoxin 1 (LcPxn1) is predominantly expressed in the amastigote 
stage, whereas LcPxn2 and LcPxn3 are expressed mainly in the 
promastigote stage, with LcPxn3 being far less abundant than LcPxn2. 
LcPxn2 and LcPxn3 possess a nine-amino acid extension at the carboxyl 
terminus, which LcPxn1 lacks. LcPxn1 appears to exist as high molecular 
weight multimers in vivo, and recombinant LcPxn1 was shown to detoxify 
hydrogen peroxide and alkyl hydroperoxides. We also present strong 
evidence that recombinant LcPxn1 can enzymatically detoxify hydroxyl 
radicals, an activity never before clearly demonstrated for a protein.




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