[leish-l] Fwd: Articles found by RefScout 30/03/2005 - 13/2005
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This is RefScout-Newsletter 13/2005.
REQUEST: [ leishmaniasis ]
(23 articles match this request. 2 articles matching other requests removed)
PMID: 15793290
TITLE: The Contribution of the Fas/FasL Apoptotic Pathway in Ulcer Formation
during Leishmania major-Induced Cutaneous Leishmaniasis.
AUTHORS: Liv Eidsmo, Susanne Nylen, Ali Khamesipour, Mari-Anne Hedblad,
Francesca Chiodi, Hannah Akuffo
AFFILIATION: MTC, Karolinska Institutet, Box 280, 171 77 Stockholm, Sweden.
liv.eidsmo at mtc.ki.se.
REFERENCE: Am J Pathol 2005 Apr 166(4):1099-108
Cutaneous leishmaniasis (CL), caused by the intracellular protozoan
Leishmania major, is characterized by lesion formation and ulceration at
the site of infection. The mechanism of ulcer formation during CL is
not fully understood. The expression of Fas and FasL and the levels of
apoptosis in skin biopsies and in restimulated blood mononuclear cells
from patients with 1 to 7 months of L. major-induced CL were analyzed
using immunohistochemistry and fluorescence-activated cell sorting
analysis. The levels of soluble Fas and FasL were also analyzed by
enzyme-linked immunosorbent assay. A substantial number of apoptotic
keratinocytes were observed mainly in the superficial epidermis of
morphologically active and healing CL skin samples. Fas expression was
increased on epidermis in active CL, whereas Fas expression was similar
in healing and healthy epidermis. FasL-expressing macrophages and T
cells were found in subepidermal infiltrate, mainly in active disease.
When CL peripheral blood mononuclear cells were restimulated with L.
major, Fas was up-regulated on effector T cells, and high levels of
sFasL were secreted. Supernatants from restimulated cultures induced
apoptosis in human keratinocytes (HaCaT), possibly through Fas/FasL
interactions. Our results indicate that FasL-expressing effector T cells
and macrophages may act to induce apoptosis and ulcer formation in Fas-
expressing keratinocytes during L. major infection.
PMID: 15792735
TITLE: Visceral leishmaniasis-an opportunistic infection in HIV-infected
patients - Authors' reply.
AUTHORS: Sarman Singh
AFFILIATION: Division of Clinical Microbiology, All India Institute of Medical
Sciences, New Delhi, India.
REFERENCE: Lancet Infect Dis 2005 Apr 5(4):197
PMID: 15791515
TITLE: Efficacy of Thermotherapy to Treat Cutaneous Leishmaniasis Caused by
Leishmania tropica in Kabul, Afghanistan: A Randomized, Controlled Trial.
AUTHORS: R Reithinger, M Mohsen, M Wahid, M Bismullah, R J Quinnell, C R Davies,
J Kolaczinski, J R David
AFFILIATION: Malaria and Leishmaniasis Control Program, HealthNet International,
University Town, Peshawar, Pakistan. rreithinger at yahoo.co.uk.
REFERENCE: Clin Infect Dis 2005 Apr 40(8):1148-55
Background. Pentavalent antimony is the agent recommended for treatment
of cutaneous leishmaniasis (CL). Its use is problematic, because it is
expensive and because of the potential for drug-associated adverse
effects during a lengthy and painful treatment course.Methods. We tested
the efficacy of thermotherapy for the treatment of CL due to Leishmania
tropica in a randomized, controlled trial in Kabul, Afghanistan. We
enrolled 401 patients with a single CL lesion and administered
thermotherapy using radio-frequency waves (1 treatment of >/=1
consecutive application at 50 degrees C for 30 s) or sodium
stibogluconate (SSG), administered either intralesionally (a total of 5
injections of 2-5 mL every 5-7 days, depending on lesion size) or
intramuscularly (20 mg/kg daily for 21 days).Results. Cure, defined as
complete reepithelialization at 100 days after treatment initiation, was
observed in 75 (69.4%) of 108 patients who received thermotherapy, 70 (
75.3%) of 93 patients who received intralesional SSG, and 26 (44.8%) of
58 patients who received intramuscular SSG. The OR for cure with
thermotherapy was 2.80 (95% confidence interval [CI], 1.45-5.41),
compared with intramuscular SSG treatment (P=.002). No statistically
significant difference was observed in the odds of cure in comparison of
intralesional SSG and thermotherapy treatments. The OR for cure with
intralesional SSG treatment was 3.75 (95% CI, 1.86-7.54), compared with
intramuscular SSG treatment (P<.001). The time to cure was
significantly shorter in the thermotherapy group (median, 53 days) than
in the intralesional SSG or intramuscularly SSG group (median, 75 days
and >100 days, respectively; P=.003).Conclusions. Thermotherapy is an
effective, comparatively well-tolerated, and rapid treatment for CL, and
it should be considered as an alternative to antimony treatment.
PMID: 15780731
TITLE: Protection against experimental visceral leishmaniasis infection in dogs
immunized with purified excreted secreted antigens of Leishmania infantum
promastigotes.
AUTHORS: Jean-Loup Lemesre, Philippe Holzmuller, Mireille Cavaleyra, Rachel Bras
Gonçalves, Grégory Hottin, Gérard Papierok
AFFILIATION: Institut de Recherche pour le Développement, UR 008 "Pathogénie
des Trypanosomatidae", 911 Avenue Agropolis, BP 64501, 34394 Montpellier cedex
5, France.
REFERENCE: Vaccine 2005 Apr 23(22):2825-40
The capacity of naturally excreted secreted antigens easily purified
from culture supernatant of Leishmania infantum promastigotes (LiESAp),
successfully cultivated in completely defined medium called CDM/LP [
Lemesre JL. Methods for the culture in vitro of different stages of
tissue parasites. International publication WO 94/26899, 1994; Merlen T
, Sereno D, Brajon N, Rostand F, Lemesre JL. Leishmania spp: completely
defined medium without serum and macromolecules (CDM/LP) for the
continuous in vitro cultivation of infective promastigote forms. Am J
Trop Med Hyg 1999;60(1):41-50] to protect dogs against experimental L.
infantum infections is described. Eighteen healthy Beagle dogs were
allocated into four groups that received at a 3-week interval either two
subcutaneous injections of 50mug (group 2, n=3), 100mug (group3, n=6)
and 200mug (group 4, n=3) LiESAp in formulation with muramyl dipeptide (
MDP) or similar injections of placebo (group 1, n=6). Dogs were
intravenously infected with 10(8) metacyclic L. infantum promastigotes.
Promastigotes of the MHOM/MA/67/ITMAP-263 and MHOM/FR/78/LEM75 strains
were, respectively, administered 2 months (at day 84, homologous
challenge 1) and 8 months post-immunization (at day 273, heterologous
challenge 2). The data indicated that vaccine candidate confers total
protection (100%) against challenges 1 and 2 in dogs from groups 3 and 4
and intermediate protection (66.7%) against challenge 1 in dogs from
group 2 as determined by parasite detection in bone marrow aspirates
during 14 months post-challenge follow-up. All placebo dogs of group 1
were found infected and failed to respond to LiESAp in cell-mediated
assays before and after both challenges. Increased levels of total anti-
leishmanial antibodies were exclusively detected in infected dogs from
group 1. Vaccine-induced protection correlates with an early
establishment of a long lasting predominantly Th1-type cellular immune
response specifically directed against LiESAp before and after
experimental infections, as demonstrated by: (i) anti-LiESAp IgG2
reactivity, and (ii) LiESAp-specific lymphocyte proliferation assays and
enhanced NO-mediated anti-leishmanial activity of canine monocyte-
derived macrophages (CM-DM) in response to higher IFNgamma production by
T-cells, when L. infantum-infected CM-DM were co-cultured with
autologous lymphocytes. Overall, our results support the view that a
LiESAp vaccine might be useful in a promising vaccination approach
against natural L. infantum infection.
PMID: 15792733
TITLE: Visceral leishmaniasis-an opportunistic infection in HIV-infected
patients.
AUTHORS: Abhijit M Bal
AFFILIATION: Department of Medical Microbiology, Aberdeen Royal Infirmary and
honorary lecturer, University of Aberdeen, Aberdeen, UK.
REFERENCE: Lancet Infect Dis 2005 Apr 5(4):196-7
PMID: 15561707
TITLE: Molecular characterization, expression, and in vivo analysis of LmexCht1:
the chitinase of the human pathogen, Leishmania mexicana.
AUTHORS: Manju B Joshi, Matthew E Rogers, Alison M Shakarian, Mat Yamage, Saeed
A Al-Harthi, Paul A Bates, Dennis M Dwyer
AFFILIATION: Cell Biology Section, Laboratory of Parasitic Diseases, NIAID,
National Institutes of Health, Bethesda, Maryland 20892-0425, USA.
REFERENCE: J Biol Chem 2005 Feb 280(5):3847-61
Chitinases have been implicated to be of importance in the life cycle
development and transmission of a variety of parasitic organisms. Using
a molecular approach, we identified and characterized the structure of a
single copy LmexCht1-chitinase gene from the primitive trypanosomatid
pathogen of humans, Leishmania mexicana. The LmexCht1 encodes an
approximately 50 kDa protein, with well conserved substrate binding and
catalytic domains characteristic of members of the chitinase-18 protein
family. Further, we showed that LmexCht1 mRNA is constitutively
expressed by both the insect vector (i.e. promastigote) and mammalian (i
.e. amastigote) life cycle developmental forms of this protozoan
parasite. Interestingly, however, amastigotes were found to secrete/
release approximately >2-4-fold higher levels of chitinase activity
during their growth in vitro than promastigotes. Moreover, a homologous
episomal expression system was devised and used to express an epitope-
tagged LmexCht1 chimeric construct in these parasites. Expression of the
LmexCht1 chimera was verified in these transfectants by reverse
transcription-PCR, Western blots, and indirect immunofluorescence
analyses. Further, results of coupled immunoprecipitation/enzyme
activity experiments demonstrated that the LmexCht1 chimeric protein was
secreted/released by these transfected L. mexicana parasites and that
it possessed functional chitinase enzyme activity. Such transfectants
were also evaluated for their infectivity both in human macrophages in
vitro and in two different strains of mice. Results of those experiments
demonstrated that the LmexCht1 transfectants survived significantly
better in human macrophages and also produced significantly larger
lesions in mice than control parasites. Taken together, our results
indicate that the LmexCht1-chimera afforded a definitive survival
advantage to the parasite within these mammalian hosts. Thus, the
LmexCht1 could potentially represent a new virulence determinant in the
mammalian phase of this important human pathogen.
PMID: 15785097
TITLE: Cross-Reaction of Sera from Patients with Various Infectious Diseases
with Leishmania infantum.
AUTHORS: Jamshid Kohanteb, Sadreddin Ardehali
AFFILIATION: Department of Microbiology, School of Medicine, Shiraz University
of Medical Sciences, Shiraz, Iran.
REFERENCE: Med Princ Pract 2005 Mar-Apr 14(2):79-82
Objective: To compare and evaluate the application of indirect
fluorescent antibody (IFA) and counterimmunoelectrophoresis (CIEP) for
laboratory identification of visceral leishmaniasis. Materials and
Methods: Serum samples from patients with malaria (Plasmodium vivax, n
= 86; Plasmodium falciparum, n = 38), brucellosis (n = 26),
tuberculosis (n = 31) and typhoid fever (n = 35) were examined for the
presence of antibody to Leishmaniainfantum antigen using IFA and CIEP
tests. Results: Using IFA, false-positive results were malaria (P. vivax
19.8%, P. falciparum 13.2%), tuberculosis (6.4%), brucellosis (3.8%),
and typhoid fever (2.8%). Using CIEP, a lower percentage of false-
positives was observed only among malaria patients (P. vivax 2.3%, P.
falciparum 2.6%). Serum samples from patients with other infectious
diseases were negative in the CIEP test. Conclusion: Based on the
results of this study, the CIEP technique is recommended for
immunodiagnosis of visceral leishmaniasis, especially in regions where
malaria, brucellosis and tuberculosis are prevalent. Copyright (c) 2005
S. Karger AG, Basel.
PMID: 15596523
TITLE: A Leishmania major response locus identified by interval-specific
congenic mapping of a T helper type 2 cell bias-controlling quantitative trait
locus.
AUTHORS: Aurelie Baguet, Jennifer Epler, Kwun W Wen, Mark Bix
AFFILIATION: Dept. of Immunology, University of Washington, 1959 N.E. Pacific
St., HSC I607I, Seattle, WA 98195, USA.
REFERENCE: J Exp Med 2004 Dec 200(12):1605-12
The propensity of naive CD4 T cells to become T helper (Th) type 2 cells
correlates with susceptibility to infection by the protozoal parasite
Leishmania major. Using genetic linkage analysis, we earlier identified
Dice1 as a Th2 cell bias-controlling quantitative trait locus on
chromosome 16. Using interval-specific congenic mapping, we now resolve
Dice1 into two independent genetic loci, Dice1.1 and Dice1.2, which
control Il4 expression from naive Th cells and thereby indirectly
control Th2 cell bias. Interestingly, only one of the two congenic
intervals containing Dice1.1 and Dice1.2, respectively, also contained
an L. major response locus, indicating that L. major responsiveness can
be insensitive to determinants that influence Th2 cell bias by
controlling naive T cell Il4 expression. These results lay the
groundwork for identifying the Dice1.1 and Dice1.2 genes controlling
naive T cell Il4 expression and L. major responses, and for testing
whether these control other Th2 cell-dependent processes such as worm
expulsion, allergic asthma, and dermatitis.
PMID: 15245745
TITLE: Visualizing the immune response to pathogens.
AUTHORS: Aparna Srinivasan, Stephen J McSorley
AFFILIATION: Department of Medicine, Division of Immunology, University of
Connecticut Health Center, Farmington, CT 06030-1319, USA.
REFERENCE: Curr Opin Immunol 2004 Aug 16(4):494-8
Advances in immune visualization have enabled the physical tracking of
immune responses in vivo. The adaptation of such technology to models of
infectious disease holds the promise of a more detailed analysis of
host-pathogen interactions in a natural setting. However, the
visualization of pathogen-specific immune responses in vivo confronts
challenges that are inherent to the study of infectious disease systems
. Recent attempts to track pathogen-specific immune responses in vivo
validate the usefulness and underline the complexity of this
experimental strategy.
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PMID: 12704145
TITLE: Amastigote load and cell surface phenotype of infected cells from lesions
and lymph nodes of susceptible and resistant mice infected with Leishmania
major.
AUTHORS: Eric Muraille, Carl De Trez, Bernard Pajak, Fabiola Aguilar Torrentera,
Patrick De Baetselier, Oberdan Leo, Yves Carlier
AFFILIATION: Laboratory of Parasitology, Université Libre de Bruxelles, Erasme,
Brussels, Belgium.
REFERENCE: Infect Immun 2003 May 71(5):2704-15
Cells of the dendritic cell (DC) lineage, by their unique ability to
stimulate naive T cells, may be of crucial importance in the development
of protective immune responses to Leishmania parasites. The aim of this
study was to compare the impact of L. major infection on DCs in BALB/c
(susceptible, developing Th2 responses), C57BL/6 (resistant, developing
Th1 responses), and tumor necrosis factor (TNF)(-/-) C57BL/6 mice (
susceptible, developing delayed and reduced Th1 responses). We analyzed
by immunohistochemistry the phenotype of infected cells in vivo.
Granulocytes (GR1(+)) and macrophages (CD11b(+)) appear as the mainly
infected cells in primary lesions. In contrast, cells expressing CD11c,
a DC specific marker, are the most frequently infected cells in draining
lymph nodes of all mice tested. These infected CD11c(+) cells harbored
a particular morphology and cell surface phenotype in infected C57BL/6
and BALB/c mice. CD11c(+) infected cells from C57BL/6 and TNF(-/-) C57BL
/6 mice displayed a weak parasitic load and a dendritic morphology and
frequently expressed CD11b or F4/80 myeloid differentiation markers. In
contrast, some CD11c(+) infected cells from BALB/c mice were
multinucleated giant cells. Giant cells presented a dramatic
accumulation of parasites and differentiation markers were not
detectable at their surface. In all mice, lymph node CD11c(+) infected
cells expressed a low major histocompatibility complex II level and no
detectable CD86 expression. Our results suggest that infected CD11c(+)
DC-like cells might constitute a reservoir of parasites in lymph nodes.
PMID: 12633653
TITLE: Leishmania (Leishmania) chagasi infection alters the expression of cell
adhesion and costimulatory molecules on human monocyte and macrophage.
AUTHORS: M C De Almeida, S A Cardoso, M Barral-Netto
AFFILIATION: Faculdade de Medicina, Universidade Federal da Bahia Gonçalo
Moniz, Fiocruz, Salvador, BA, Brazil. marcalmo at unb.br
REFERENCE: Int J Parasitol 2003 Feb 33(2):153-62
The initial steps of Leishmania infection in humans are largely unknown
. There is limited information on the Leishmania infected human
monocytes, the first cells that the parasite lives in, particularly
related to costimulatory molecules. We show here that Leishmania (L.)
chagasi infection avoids inducing proinflammatory molecules and has
striking down modulating effects on human monocytes or macrophages. It
does not induce CD54, interleukin (IL)-12 or tumour necrosis factor-
alpha, potent proinflammatory cytokines and down modulates CD11b
expression in monocytes. Lipopolysaccharide stimulated IL-12 (p40)
levels, CD54 and HLA-DR expression are diminished in infected monocytes
as well as interferon-gamma stimulated HLA-DR and HLA-ABC expression in
infected macrophages. There is a negative correlation between CD54 and
CD86 expression in both monocytes and macrophages. The depressed
expression of class I and II molecules, absence of key proinflammatory
cytokines and impaired expression of costimulatory molecules induced by
L. chagasi could leave the immune system, at least in its initial phases
in anergy or ignorance.
PMID: 12574369
TITLE: NF-kappa B1 is required for optimal CD4+ Th1 cell development and
resistance to Leishmania major.
AUTHORS: David Artis, Kendra Speirs, Karen Joyce, Michael Goldschmidt, Jorge
Caamaño, Christopher A Hunter, Phillip Scott
AFFILIATION: Department of Pathobiology, School of Veterinary Medicine,
University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104, USA.
REFERENCE: J Immunol 2003 Feb 170(4):1995-2003
The NF-kappaB family of transcription factors regulates the expression
of a wide range of immune response genes involved in immunity to
pathogens. However, the need for individual family members in regulating
innate and adaptive immune responses in vivo has yet to be clearly
defined. We investigated the role of NF-kappaB1 in the induction of
protective IL-12-dependent Th1 cell responses following infection with
the intracellular protozoan parasite Leishmania major. Whereas wild-type
C57BL/6 mice controlled parasite replication, NF-kappaB1 knockout (KO)
mice were susceptible to infection, developing chronic unresolving
lesions associated with persistent parasites. There was a profound
defect in Ag-specific CD4(+) T cell proliferation and IFN-gamma
production in infected KO mice, although innate responses-including IL-
12 production and control of intracellular parasite replication by
macrophages-were intact. In vitro polyclonal stimulation of purified
naive KO T cells revealed an intrinsic defect in CD4(+) T cell
proliferation associated with reduced IL-2 receptor expression, but
operating independently of APC function and IL-2 production. Critically
, the frequency of proliferating KO CD4(+) T cells secreting IFN-gamma
matched that of wild-type cells, suggesting that NF-kappaB1 was not
required for efficient transcription of the IFN-gamma gene. Taken
together, these results identify a novel role for NF-kappaB1 in CD4(+) T
cell proliferation and the development of Th1 cell responses required
for protective immunity against intracellular pathogens.
PMID: 12516542
TITLE: Blockade of CD86 in BALB/c mice infected with Leishmania major does not
prevent the expansion of low avidity T cells.
AUTHORS: Monica Moro, Christophe Filippi, Alexandra Gallard, Laurent Malherbe,
Gilles Foucras, Hisaya Akiba, Hideo Yagita, Jean-Charles Guéry, Nicolas
Glaichenhaus
AFFILIATION: Centre National de la Recherche Scientifique, Valbonne, France.
REFERENCE: Eur J Immunol 2002 Dec 32(12):3566-75
The interactions between CD28 and its ligand CD86 are critical for the
regulation of T cell responses. However, it is not clear whether CD4+ T
cells expressing low and high avidity TCR are equally dependent on CD28
costimulation for their activation and expansion. To address this issue
, we have used multimers of I-Ad molecules linked to a peptide derived
from the Leishmania major homolog for the receptor of activated C kinase
(LACK) antigen to compare the fate of LACK-specific CD4+ T cells in
Leishmania-infected BALB/c mice which have been treated or not with anti
-CD86 mAb. Although the administration of anti-CD86 mAb did not
completely prevent the expansion of LACK-specific T cells, their
frequency and number were markedly reduced. In mice treated with anti-
CD86 mAb as well as in control animals, L. major induced the clonal
expansion of LACK-specific T cells which expressed a canonical low
avidity Valpha8/Vbeta4 TCR. Taken together, our results suggest that the
molecular interactions between CD28 on T cells and CD86 on APC serve to
amplify and modulate T cell responses without promoting breadth in the
TCR repertoire.
PMID: 12115660
TITLE: T helper differentiation in resistant and susceptible B7-deficient mice
infected with Leishmania major.
AUTHORS: Julia A Brown, Rebecca J Greenwald, Sumi Scott, A Nicola Schweitzer,
Abhay R Satoskar, Charles Chung, Lisa R Schopf, Diane van der Woude, Joseph P
Sypek, Arlene H Sharpe
AFFILIATION: Department of Pathology, Immunology Research Division, Brigham and
Women's Hospital, Boston, MA, USA.
REFERENCE: Eur J Immunol 2002 Jun 32(6):1764-72
The contribution of the costimulatory molecules B7-1 and B7-2 to the in
vivo differentiation of Th cells remains controversial. The infection of
resistant and susceptible strains of mice with the parasite Leishmania
major provides a well-established model for studying in vivo
differentiation of CD4+ T cells. We have infected B7-1/B7-2-deficient
mice on the BALB/c and 129 background with L. major and subsequently
examined different parameters of infection and cytokine responses upon
restimulation of lymph node cells in vitro. BALB/c B7-2-deficient and B7
-1/B7-2-double deficient mice are resistant to L. major, whereas BALB/c
B7-1-deficient mice remain as susceptible as wild-type BALB/c mice.
Differential expression of B7-1 and B7-2 can explain the distinct roles
observed for these B7 costimulators in L. major infection.
PMID: 11694036
TITLE: Experimental leishmaniasis: the glibenclamide-triggered decrease in
parasite growth correlates with changes in macrophage features.
AUTHORS: A Ponte-Sucre, K Figarella, H Moll
AFFILIATION: Laboratory of Molecular Physiology, Instituto de Medicina
Experimental, Facultad de Medicina, Universidad Central de Venezuela, Caracas.
aiponte at reacciun.ve
REFERENCE: Immunopharmacol Immunotoxicol 2001 Aug 23(3):477-86
Previous studies from our laboratories revealed the susceptibility of
Leishmania sp. to glibenclamide (GLIB), a potassium channel blocker
which selectively interacts with adenosine-binding-cassette transporters
. In the present work, we analyzed whether the drug sensitivity of
intracellular amastigotes correlates with changes in macrophage features
that are related to their function as antigen-presenting cells. We
provide evidence that in BALB/c murine macrophages, GLIB induced a
decrease in the interferon-gamma-stimulated expression of major
histocompatibility complex class II molecules and the co-stimulatory
molecule CD86 (B7-2). Furthermore, it caused a decrease in the
interleukin-1 secretion by macrophages. The data indicate that the
treatment with GLIB inhibits the Th2 development and polarizes
macrophage functions towards the induction of a protective Th1 response.
PMID: 10820265
TITLE: IL-12p70 production by Leishmania major-harboring human dendritic cells
is a CD40/CD40 ligand-dependent process.
AUTHORS: M A Marovich, M A McDowell, E K Thomas, T B Nutman
AFFILIATION: Laboratory of Parasitic Diseases, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
REFERENCE: J Immunol 2000 Jun 164(11):5858-65
Leishmaniasis, a vector-borne parasitic disease, is transmitted during a
sandfly blood meal as the parasite is delivered into the dermis. The
parasite displays a unique immune evasion mechanism: prevention of IL-12
production within its host cell, the macrophage (i.e., where it
differentiates and multiplies). Given the close proximity of skin
dendritic cells (DC) to the site of parasite delivery, their critical
role in initiating immune responses and the self-healing nature of
Leishmania major (Lm) infection, we examined the interaction between
myeloid-derived human DC and Lm metacyclic promastigotes (infectious-
stage parasites) to model the early "natural" events of
infection. We found that DC can take up Lm and, after this
internalization, undergo changes in surface phenotype suggesting "
maturation". Despite the intracellular location of the parasite and
resultant up-regulation of costimulatory and class II molecules, there
was no detectable cytokine release by these Lm-harboring DC. However,
using intracellular staining and flow cytometry to analyze cytokine
production at the single-cell level, we found that Lm-harboring DC, but
not monocytes, produce large amounts of IL-12p70 in a CD40 ligand (CD40L
)-dependent manner. Finally, DC generated from mononuclear cells from
patients with cutaneous leishmaniasis (Lm), once loaded with live
metacyclic promastigotes, were found to reactivate autologous primed T
lymphocytes and induce a CD40L-dependent IFN-gamma response. Our results
link the required CD40/CD40L interactions for healing with DC-derived
IL-12p70 production and provide a mechanism to explain the genesis of a
protective T cell-mediated response in the face of local immune evasion
within the macrophage at the site of Leishmania delivery.
PMID: 10605608
TITLE: The host response to Leishmania infection.
AUTHORS: W Solbach, T Laskay
AFFILIATION: Institute for Medical Microbiology and Hygiene, University of
Luebeck, Germany.
REFERENCE: Adv Immunol 2000 74():275-317
PMID: 10352289
TITLE: Expression and contribution of B7-1 (CD80) and B7-2 (CD86) in the early
immune response to Leishmania major infection.
AUTHORS: M M Elloso, P Scott
AFFILIATION: Department of Pathobiology, University of Pennsylvania School of
Veterinary Medicine, Philadelphia 19104, USA.
REFERENCE: J Immunol 1999 Jun 162(11):6708-15
CD28 interactions promote T cell responses, and whether B7-1 or B7-2 is
utilized may influence Th cell subset development. CD28 blockade by CTLA
-4Ig treatment or by targeted gene disruption has yielded different
conclusions regarding the role of CD28 in the development of Th1 and Th2
cells following Leishmania major infection. In this study, we
demonstrate that B7-mediated costimulation is required for the
development of the early immune response following infection of
resistant or susceptible mice. In contrast, CD28-/- BALB/c mice infected
with L. major produce cytokines comparable to those of infected wild-
type mice. Treatment of CD28-/- mice with CTLA-4Ig did not diminish this
response, suggesting that a B7-independent pathway(s) contributes to
the early immune response in these mice. In conventional BALB/c or C3H
mice, B7-2 functions as the dominant costimulatory molecule in the
initiation of early T cell activation following L. major infection,
leading to IL-4 or IFN-gamma production, respectively. The preferential
interaction of B7-2 with its ligand(s) in the induction of these
responses correlates with its constitutive expression relative to that
of B7-1. However, B7-1 can equally mediate costimulation for the
production of either IL-4 or IFN-gamma when expressed at high levels.
Thus, in leishmaniasis, costimulation involving B7-1 or B7-2 can result
in the production of either Th1 or Th2 cytokines, rather than a
preferential induction of one type of response.
PMID: 9379045
TITLE: B7-2 blockade enhances T cell responses to Leishmania donovani.
AUTHORS: M L Murphy, C R Engwerda, P M Gorak, P M Kaye
AFFILIATION: Department of Infectious and Tropical Diseases, London School of
Hygiene and Tropical Medicine, United Kingdom.
REFERENCE: J Immunol 1997 Nov 159(9):4460-6
Infection with Leishmania donovani has been reported to induce a
dominant Th1-type response in all strains of mice examined, providing a
model for examining the regulation of Th1 responses in the relative
absence of Th2 cross-regulation. Here we demonstrate that blockade of
the costimulatory molecule B7-2, but not B7-1, has significant effects
on disease progression, measured as day 28 parasite burden in the liver
. The effects of B7-2 blockade were associated with increased IFN-gamma
production, as determined 1) following restimulation with specific Ag, 2
) by enumeration of IFN-gamma-secreting cells using ELISPOT assays, and
3) by analysis of IFN-gamma mRNA by reverse transcription-PCR.
Surprisingly, IL-4-producing cells were also readily detected in
infected mice by ELISPOT analysis. The frequency of these IL-4-producing
cells and of IL-4 mRNA levels was also enhanced in the liver of
infected mice treated with anti-B7-2 mAb. Administration of anti-B7-2
from the day of infection or delaying its administration until day 3
after infection had similar effects. Parasite-specific IgG1 and IgG2a
responses were either unaffected or marginally increased following anti-
B7-2 administration, contrary to the inhibitory effect of this treatment
on responses to the T-dependent Ag DNP-BSA. These data support a model
of T cell activation whereby B7-2/CD28 interactions play a relatively
redundant role in initial T cell activation, but in which interference
with later B7-2/CTLA4 interaction potentiates established cytokine
responses.
PMID: 8940222
TITLE: Blockade of CD86 ameliorates Leishmania major infection by
down-regulating the Th2 response.
AUTHORS: J A Brown, R G Titus, N Nabavi, L H Glimcher
AFFILIATION: Department of Cancer Biology, Harvard School of Public Health,
Boston, Massachusetts 02115, USA.
REFERENCE: J Infect Dis 1996 Dec 174(6):1303-8
The costimulatory molecules CD80 and CD86 affect the differentiation of
Th1 and Th2 subsets in experimental allergic encephalomyelitis, an
autoimmune disorder. It is reported that the CD86 costimulator
significantly affects disease outcome in Leishmania major infection, a
classic model of Th subset polarization. Treatment of both L. major-
resistant (C57BL/6) and susceptible (BALB/c) strains of mice with anti-
CD86 substantially decreased parasite burden. This was accompanied, in
BALB/c mice, by a decrease in Th2 cytokines. In contrast, anti-CD80
treatment did not affect parasite burden or cytokine levels in either
strain. These data illustrate that in L. major infection, anti-CD86 can
abrogate Th2 differentiation in a Th2-dominated susceptible mouse and
can ameliorate disease in a Th1-dominated resistant strain, although the
mechanism involved in the latter is not clear. It is concluded that in
L. major infection, Th2 subset differentiation is critically dependent
on interaction with the CD86 costimulatory molecule.
PMID: 8102156
TITLE: Antigen presentation capacity of murine macrophages infected with
Leishmania amazonensis amastigotes.
AUTHORS: E Prina, C Jouanne, S de Souza Lão, A Szabo, J G Guillet, J C Antoine
AFFILIATION: Unité d'Immunophysiologie Cellulaire, Institut Pasteur, Paris,
France.
REFERENCE: J Immunol 1993 Aug 151(4):2050-61
Leishmania-infected M phi are potential candidates for the presentation
of parasite Ag to Leishmania-specific CD4+ T lymphocytes. To assess
whether infected cells could function as APC, we examined the ability of
bone marrow-derived M phi infected with Leishmania amazonensis
amastigotes to stimulate various CD4+, l-Ad- or l-Ed-restricted T-cell
hybridomas specific for the bacteriophage lambda repressor cl protein,
the human chorionic gonadotropin or OVA. A reduced capacity of infected
M phi to present native Ag to most T-cell hybridomas tested was noted
that was probably a result of a lower expression on their plasma
membrane of stimulatory [la-peptide] complexes. Neither a reduced Ag
uptake nor an altered Ag processing appeared to be at the origin of the
partial inability of infected M phi to present Ag. As regards the level
of plasma membrane la expression, no quantitative difference could be
detected between uninfected and infected M phi. Moreover, after fixation
with paraformaldehyde, the ability of plasma membrane la molecules to
bind immunogenic peptides was apparently not reduced in infected M phi.
So, these cells most likely expressed functional la molecules on their
cell surface. Interestingly, infected M phi and M phi infected then
cured by a treatment with a leishmanicidal compound were similarly
impaired in their capacity to present native Ag or peptides to the
hybridomas, and no recovery was noted even 24 h after the leishmanicidal
treatment. Furthermore, infected M phi and M phi incubated with heat-
killed amastigotes or with an amastigote homogenate exhibited similar
inhibitions of Ag presentation. Taken together, these results suggest
that the functional failure of infected M phi to present exogenous Ag
could be because either of interferences with the events leading to the
meeting of la molecules with peptides derived from these exogenous Ag or
to a competition for binding to la molecules between these peptides and
parasite molecules.
REQUEST: [ leishmania ]
(29 articles match this request. 20 articles matching other requests removed)
PMID: 15781271
TITLE: The overexpression of an intracellular ABCA-like transporter alters
phospholipid trafficking in Leishmania.
AUTHORS: José MarÃa Araújo-Santos, Adriana Parodi-Talice, Santiago Castanys,
Francisco Gamarro
AFFILIATION: Instituto de ParasitologÃa y Biomedicina "López-Neyra", C.S.I.C,
Parque Tecnológico de Ciencias de la Salud, Avda del Conocimiento s/n 18100
Armilla, Granada, Spain.
REFERENCE: Biochem Biophys Res Commun 2005 Apr 330(1):349-55
In parasites, ATP-binding cassette (ABC) transporters represent an
important family of proteins related to drug resistance and other
biological activities. Here we report the characterization of LtrABCA2,
a new ABC transporter of the ABCA subfamily in the protozoan parasite
Leishmania tropica, localized at the flagellar pocket region and in
internal vesicles. The overexpression of this transporter reduced the
accumulation of fluorescent glycerophospholipid analogs, increased the
exocytic activity, and decreased infectivity of macrophage, but did not
confer resistance to drugs. Together, these results suggest that this
new ABC transporter plays a role in phospholipid trafficking, which may
be modifying the vesicular trafficking and the infectivity of the
parasite.
PMID: 15784551
TITLE: Interleukin 10- and Fc{gamma} Receptor-Deficient Mice Resolve Leishmania
mexicana Lesions.
AUTHORS: Laurence U Buxbaum, Phillip Scott
AFFILIATION: Department of Pathobiology, University of Pennsylvania School of
Veterinary Medicine, 216 ROS, 3800 Spruce Street, Philadelphia, PA 19104.
pscott at vet.upenn.edu.
REFERENCE: Infect Immun 2005 Apr 73(4):2101-8
Infection of C57BL/6 (B6) mice with Leishmania mexicana is associated
with a minimal immune response and chronic disease. Here we show that B6
interleukin 10(-/-) (IL-10(-/-)) mice resolve their lesions and exhibit
increased gamma interferon (IFN-gamma), nitric oxide production, and
delayed-type hypersensitivity. This enhanced resistance was dependent
upon IL-12p40, since treatment of L. mexicana-infected IL-10(-/-) mice
with anti-IL-12p40 monoclonal antibody abrogated healing. Antibody-
opsonized L. mexicana induced IL-10 production by B6 macrophages in
vitro, implicating antibody binding to Fc receptors as a mechanism
involved in IL-10 production in this infection. Furthermore, B6 FcRgamma
(-/-) mice resolve L. mexicana lesions, and lymph node cells from these
mice produced less IL-10 and more IFN-gamma than cells from infected
wild-type mice. These data demonstrate that removal of IL-10 or FcgammaR
leads to resolution of L. mexicana disease and support a model in which
ligation of FcgammaR by L. mexicana-bound immunoglobulin G promotes IL-
10 production, leading to chronic disease.
PMID: 15793124
TITLE: Topoisomerase I Amino Acid Substitutions, Gly185Arg and Asp325Glu, Confer
Camptothecin Resistance in Leishmania donovani.
AUTHORS: Jean-François Marquis, Isabelle Hardy, Martin Olivier
AFFILIATION: Department of Microbiology and Immunology, McGill University, Lyman
Duff Building, 3775 University St., Room 600, Montréal, Québec, Canada H3A
2B4. martin.olivier at mcgill.ca.
REFERENCE: Antimicrob Agents Chemother 2005 Apr 49(4):1441-6
The antitumor compound camptothecin (CPT) is also recognized for its
specific activity against Leishmania donovani topoisomerase I (Topo-I).
In consequence, defining CPT resistance mechanisms represents an
important strategic tool in the acquisition of a better understanding of
its mode of action. In the present study, we selected a single highly
resistant L. donovani strain termed LdRCPT.160 by stepwise exposure to
CPT. Gene sequencing revealed two single nucleotide mutations in the
LdRCPT.160 LdTOP1A gene, resulting in two amino acid substitutions (
Gly185Arg and Asp325Glu) in the protein. Moreover, these two
substitutions observed in the LdTOP1A protein were correlated with a
decreased Topo-I DNA relaxation activity in these resistant parasites.
Nevertheless, there was no change in the LdTOP1A gene expression level.
Interestingly, transfection studies of the LdRCPT.160 LdTOP1A gene in
its wild-type counterpart showed that it induced CPT resistance. Site-
directed mutagenesis studies demonstrated that, despite a substantial
level of resistance conferred by the Gly185Arg and Asp325Glu
substitutions separately, both were essential to reach a high-resistance
phenotype. Of interest, the amino acid substitutions observed in LdRCPT
.160 LdTOP1A protein occurred near the amino acids previously predicted
to interact with CPT, providing new insight into the mechanism of CPT
molecular action.
PMID: 15784607
TITLE: Leishmania major Modulates Chemokine and Chemokine Receptor Expression by
Dendritic Cells and Affects Their Migratory Capacity.
AUTHORS: Mario Steigerwald, Heidrun Moll
AFFILIATION: Institut für Molekulare Infektionsbiologie, Universität
Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
heidrun.moll at mail.uni-wuerzburg.de.
REFERENCE: Infect Immun 2005 Apr 73(4):2564-7
Dendritic cells (DC) both produce and respond to chemokines. We examined
the profiles of chemokines and chemokine receptors expressed by DC and
their chemotactic response after interaction with Leishmania major.
Expression of the chemokine receptors CCR2 and CCR5 by DC and their
responsiveness to the respective ligands, CCL2 and CCL3, were
downregulated, while the level of CCR7 and the DC response to its ligand
CCL21 were enhanced. These parasite-induced alterations were observed
with DC from L. major-resistant and -susceptible mice. In contrast,
expression of the chemokine CXCL10 was elicited only in DC from L. major
-resistant mice.
PMID: 15789648
TITLE: Efficacy of the treatment of dogs with leishmaniosis with a combination
of metronidazole and spiramycin.
AUTHORS: M G Pennisi, M De Majo, M Masucci, D Britti, F Vitale, R Del Maso
AFFILIATION: Dipartimento di Scienze Mediche Veterinarie, Università degli
Studi di Messina, Messina, Italy.
REFERENCE: Vet Rec 2005 Mar 156(11):346-9
Twenty-seven dogs infected naturally with Leishmania infantum were used
in a randomised controlled trial to compare the clinical and
parasitological efficacy of an oral treatment with a combination of
metronidazole and spiramycin (13 dogs) with the efficacy of conventional
treatment with meglumine antimonate and allopurinol (14 dogs) as
controls. In the test group one dog had to be withdrawn from the
treatment because it developed pemphigus foliaceus; 10 of the dogs were
clinically responsive but none was cured parasitologically. In the
control group four dogs were withdrawn from the treatment because of
side effects; eight of the dogs were clinically responsive but none was
cured parasitologically. The control group showed signs of improvement
after an average of 30 days, whereas the test group did not show signs
of improvement until after an average of 45 days.
PMID: 15781496
TITLE: Formation of linear inverted repeat amplicons following targeting of an
essential gene in Leishmania.
AUTHORS: Paul-André Genest, Bas ter Riet, Carole Dumas, Barbara Papadopoulou,
Henri G A M van Luenen, Piet Borst
AFFILIATION: Division of Molecular Biology and Centre of Biomedical Genetics,
The Netherlands Cancer Institute Plesmanlaan 121, 1066 CX Amsterdam, The
Netherlands.
REFERENCE: Nucleic Acids Res 2005 33(5):1699-709
Attempts to inactivate an essential gene in the protozoan parasite
Leishmania have often led to the generation of extra copies of the wild-
type alleles of the gene. In experiments with Leishmania tarentolae set
up to disrupt the gene encoding the J-binding protein 1 (JBP1), a
protein binding to the unusual base beta-D-glucosyl-hydroxymethyluracil
(J) of Leishmania, we obtained JBP1 mutants containing linear DNA
elements (amplicons) of approximately 100 kb. These amplicons consist of
a long inverted repeat with telomeric repeats at both ends and contain
either the two different targeting cassettes used to inactivate JBP1, or
one cassette and one JBP1 gene. Each long repeat within the linear
amplicons corresponds to sequences covering the JBP1 locus, starting at
the telomeres upstream of JBP1 and ending in a approximately 220 bp
sequence repeated in an inverted (palindromic) orientation downstream of
the JBP1 locus. We propose that these amplicons have arisen by a
template switch inside a DNA replication fork involving the inverted DNA
repeats and helped by the gene targeting.
********************************************************************************************************************
The following references are revised files and are brought to you in accordance
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********************************************************************************************************************
PMID: 15102766
TITLE: Leishmania major amastigotes induce p50/c-Rel NF-kappa B transcription
factor in human macrophages: involvement in cytokine synthesis.
AUTHORS: Lamia Guizani-Tabbane, Khadija Ben-Aissa, Meriam Belghith, Atfa Sassi,
Koussay Dellagi
AFFILIATION: Laboratory of Immunology, Vaccinology and Molecular Genetics (WHO
Collaborating Center for Research and Training in Leishmaniasis), Institut
Pasteur de Tunis, 1002 Tunis-Belvedere, Tunisia. lamia.guizani at Pasteur.rns.tn
REFERENCE: Infect Immun 2004 May 72(5):2582-9
Invasion of a host by pathogens is frequently associated with activation
of nuclear factor kappa B (NF-kappaB), which is implicated in various
aspects of immune function required for resistance to infection. However
, pathogens may also subdue these mechanisms to secure their survival.
Here we describe the effect of Leishmania major infection on NF-kappaB
transcription factor activation in both promonocytic human cell line
U937 and fresh human monocytes. Infection by L. major amastigotes
blocked nuclear translocation of a phorbol-12 myristate-13 acetate (PMA
)-induced p50/p65 NF-kappaB complex in PMA-treated differentiated U937
cells and triggered expression of p50- and c-Rel-containing complexes in
both U937 cells and fresh human monocytes. These p50/c-Rel complexes,
triggered by direct cell-parasite interactions, were detectable within
30 min after the interaction and were transcriptionally active. The NF-
kappaB inhibitor caffeic acid phenethyl ester inhibited production of
both tumor necrosis factor alpha and interleukin-10 (IL-10) induced by
Leishmania amastigotes in differentiated U937 cells. Similar results for
IL-10 induction were observed with amastigote-infected human monocytes
. Our results indicate that L. major amastigotes activate NF-kappaB by
specifically inducing p50- and c-Rel-containing complexes which are
likely involved in the regulation of cytokine synthesis.
PMID: 12097397
TITLE: Human neutrophil-expressed CD28 interacts with macrophage B7 to induce
phosphatidylinositol 3-kinase-dependent IFN-gamma secretion and restriction of
Leishmania growth.
AUTHORS: K Venuprasad, Pinaki P Banerjee, Subhasis Chattopadhyay, Satyan Sharma,
Subrata Pal, P B Parab, Debashis Mitra, Bhaskar Saha
AFFILIATION: National Center for Cell Science, Ganeshkhind, India.
REFERENCE: J Immunol 2002 Jul 169(2):920-8
We previously showed that CD28 is expressed on human peripheral blood
neutrophils and plays an important role in CXCR-1 expression and IL-8-
induced neutrophil migration. In this work we demonstrate that
Leishmania major infection of macrophages results in parasite dose-
dependent IL-8 secretion in vitro and in IL-8-directed neutrophil
migration, as blocked by both anti-IL-8 and anti-IL-8R Abs, toward the L
. major-infected macrophages. In the neutrophil-macrophage cocultures,
both CTLA4-Ig, a fusion protein that blocks CD28-CD80/CD86 interaction,
and a neutralizing anti-IFN-gamma Ab inhibit the anti-leishmanial
function of neutrophils, suggesting that the neutrophil-macrophage
interaction via CD28-CD80/CD86 plays an important role in the IFN-gamma-
dependent restriction of the parasite growth. Cross-linking of
neutrophil-expressed CD28 by monoclonal anti-CD28 Ab or B7.1-Ig or B7.2-
Ig results in phosphatidylinositol 3-kinase association with CD28 and in
wortmannin-sensitive but cyclosporin A-resistant induction and
secretion of IFN-gamma. Whereas the neutrophils secrete IFN-gamma with
CD28 signal alone, the T cells do not secrete the cytokine in detectable
amounts with the same signal. Thus, neutrophil-expressed CD28 modulates
not only the granulocyte migration but also induction and secretion of
IFN-gamma at the site of infection where it migrates from the
circulation.
PMID: 11159953
TITLE: Influence of costimulatory molecules on immune response to Leishmania
major by human cells in vitro.
AUTHORS: C I Brodskyn, G K DeKrey, R G Titus
AFFILIATION: Department of Pathology, College of Veterinary Medicine and
Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523,
USA.
REFERENCE: Infect Immun 2001 Feb 69(2):665-72
The importance of CD40, CD80, and CD86 costimulatory molecules in anti-
Leishmania immune responses has been established in murine models. A
role for these costimulatory molecules in human anti-Leishmania immune
responses was investigated in this study. Autologous macrophages and
peripheral blood leukocytes (PBL) were prepared from peripheral blood
mononuclear cells of Leishmania-naive donors and cultured with or
without Leishmania major in various combinations. After 7 days of
culture, high levels of CD40 and CD86 were expressed on macrophages in
the presence or absence of L. major. When macrophages were cultured for
an additional 7 days with PBL, expression of all three costimulatory
molecules was detected. When L. major was present in these cultures, the
expression of CD80, and to a lesser extent CD40, on macrophages was
enhanced. Blockade of CD80, CD86, or both molecules (in the order of
greatest effect) in cultures containing macrophages, PBL, and L. major
significantly inhibited the production of gamma interferon, interleukin-
5 (IL-5), and IL-12. Blockade of CD40-CD154 interactions also
significantly inhibited production of these cytokines in response to L.
major. Production of IL-10 was unaltered by the blockade of these
costimulatory molecules. Thus, these data suggest that CD40, CD80, and
CD86 expression and regulation may significantly impact anti-Leishmania
immune responses in humans.
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REQUEST: [ sandfly ]
(1 article matches this request. 1 article matching other requests removed)
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