[leish-l] Fwd: Articles found by RefScout 23/03/2005 12/2005
jeffreyj at usp.br
jeffreyj at usp.br
Wed Mar 23 20:48:50 BRT 2005
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Date: Wed, 23 Mar 2005 15:13:39
From: info at refscout.com
This is RefScout-Newsletter 12/2005.
REQUEST: [ leishmaniasis ]
(23 articles match this request. 2 articles matching other requests removed)
PMID: 15766869
TITLE: Expression, purification, and characterization of Leishmania donovani
trypanothione reductase in Escherichia coli.
AUTHORS: Mukul K Mittal, Smita Misra, Mohammad Owais, Neena Goyal
AFFILIATION: Division of Biochemistry, Central Drug Research Institute, Lucknow,
India.
REFERENCE: Protein Expr Purif 2005 Apr 40(2):279-86
Trypanothione reductase (TR) is an NADPH-dependent flavoprotein
oxidoreductase central to thiol metabolism in all the trypanosomatids
including Leishmania. The unique presence of this enzyme in
trypanosomatids and absence in mammalian host make this enzyme an
attractive target for the development of the antileishmanials. Complete
open reading frame encoding trypanothione reductase from Leishmania
donovani (Dd8 strain, causative agent of Indian visceral leishmaniasis)
was cloned, sequenced, and expressed in Escherichia coli strain BL21 (
DE3) as glutathione S-transferase fusion protein. The conditions were
developed for overexpression of fusion protein in soluble form and
purification of the recombinant protein to homogeneity. The recombinant
LdTR was 54.68kDa in size, dimeric in nature, and reduces oxidized
trypanothione to reduced form. The kinetic parameters for trypanothione
disulfide are K(m), 50muM; k(cat), 18,181min(-1); and k(cat)/K(m), 6.
06x10(6)M(-1)s(-1). The yield of recombinant LdTR was approximately 16mg
/L bacterial culture and accounted for 6% of the total soluble proteins
. The expressed protein was inhibited by known TR inhibitors as well as
by SbIII, the known antileishmanial compound. This is the first report
of large-scale production of any leishmanial TR in E. coli.
PMID: 15750095
TITLE: Leishmania promastigote membrane antigen-based enzyme-linked
immunosorbent assay and immunoblotting for differential diagnosis of Indian
post-kala-azar dermal leishmaniasis.
AUTHORS: Samiran Saha, Tuhina Mazumdar, Khairul Anam, Rajesh Ravindran, Bibhas
Bairagi, Bibhuti Saha, Ramapada Goswami, Netai Pramanik, Subhashis K Guha,
Sourjya Kar, Dwijadas Banerjee, Nahid Ali
AFFILIATION: Indian Institute of Chemical Biology, 4, Raja. S. C. Mullick Rd.,
Calcutta 700032, India.
REFERENCE: J Clin Microbiol 2005 Mar 43(3):1269-77
Diagnosis of post-kala-azar dermal leishmaniasis (PKDL), caused by
Leishmania donovani, is difficult, as the dermal lesions are of several
types and resemble those caused by other skin diseases, especially
leprosy. Since the disease generally appears very late after the
clinical cure of kala-azar in India, it is also difficult to correlate
PKDL with a previous exposure to L. donovani. Very few attempts have
been made so far to diagnose PKDL serologically, and the diagnostic
methods vary in their sensitivities and specificities. Diagnosis of PKDL
through sophisticated PCR methods, although highly sensitive, has
limited practical use. We have developed a serodiagnostic method using
an enzyme-linked immunosorbent assay to detect specific immunoglobulin (
Ig) isotypes and IgG subclass antibodies in the sera of Indian PKDL
patients. Our assay, which uses L. donovani promastigote membrane
antigens, was 100% sensitive for the detection of IgG and 96.7% specific
for the detection of IgG and IgG1. Optical density values for
individual patients, however, demonstrated wide variations. Western blot
analysis based on IgG reactivity could differentiate patients with PKDL
from control subjects, which included patients with leprosy, patients
from areas where kala-azar is endemic, and healthy subjects, by the
detection of polypeptides of 67, 72, and 120 kDa. The recognition
patterns of the majority of serum samples from patients with PKDL were
also distinct from those of the serum samples from patients with
visceral leishmaniasis (VL), at least for a 31-kDa polypeptide. To
further differentiate patients with PKDL from those with active and
cured VL, we analyzed the specific titers of the Ig isotypes and IgG
subclasses. High levels of IgG, IgG1, IgG2, and IgG3 antibodies
significantly differentiated patients with PKDL from patients cured of
VL. The absence of antileishmanial IgE and IgG4 in patients with PKDL
differentiated these patients from those with active VL. These results
imply intrinsic differences in the antibodies generated in the sera from
patients with PKDL and VL.
PMID: 15766604
TITLE: Leishmania (Viannia) subgenus kDNA amplification for the diagnosis of
mucosal leishmaniasis.
AUTHORS: Jolande Disch, Mariana Junqueira Pedras, Marcela Orsini, Claude Pirmez,
Maria Cláudia de Oliveira, Marcelo Castro, Ana Rabello
AFFILIATION: Laboratory of Clinical Research, Centro de Pesquisas René Rachou,
Fundação Oswaldo Cruz (FIOCRUZ), Belo Horizonte, MG 30190-002, Brazil.
REFERENCE: Diagn Microbiol Infect Dis 2005 Mar 51(3):185-90
The utility of 2 polymerase chain reaction (PCR)-based assays amplifying
genus or Viannia subgenus Leishmania minicircle kDNA for the
diagnostics of ML was assessed. The Viannia subgenus product was yielded
after PCR from isolates of L. (Viannia) braziliensis, L. (Viannia)
colombiensis, and L. (Viannia) guyanensis, whereas no product was
obtained with the non-Viannia-pertaining species: L. (Leishmania)
amazonensis, L. (Leishmania) donovani, and L. (Leishmania) chagasi. With
both assays, 11 of 13 (86.4%) patients with confirmed ML could be
identified, whereas only 2 (16.7%) of these patients were positive by
microscopy. All amplified genus-specific products gave a positive signal
by hybridization with a Leishmania (Viannia) subgenus-specific
radioactive probe. The Viannia subgenus-specific kDNA PCR represents a
sensitive and specific tool for the diagnosis of ML, remarkably
improving the sensitivity of parasitological methods and offering an
alternative for the radioactive-dependent assays for subgenus
characterization.
PMID: 15752175
TITLE: Micro-geographical variation among male populations of the sandfly,
Lutzomyia (Nyssomyia) intermedia, from an endemic area of American cutaneous
leishmaniasis in the state of Rio de Janeiro, Brazil.
AUTHORS: C R V Meneses, E Cupolillo, F Monteiro, E F Rangel
AFFILIATION: Departamento de Entomologia, Instituto Oswaldo Cruz, Rio de
Janeiro, Brazil.
REFERENCE: Med Vet Entomol 2005 Mar 19(1):38-47
The genetic relationships among male Lutzomyia (Nyssomyia) intermedia (
Lutz & Neiva) (Diptera: Psychodidae) from three populations from the
same endemic area of American cutaneous leishmaniasis (ACL) in the
state of Rio de Janeiro, Brazil, were compared. The sandflies were
collected in three ecologically different habitats: domestic, extra-
domestic and sylvatic over a total range of 800 m. Three molecular
markers were employed to assess population variation. Based on MLEE
markers, it could not be concluded that the three populations do not
belong to the same gene pool (F(st) = 0.005). No within-population
departure from Hardy-Weinberg equilibrium was detected (P < 0.05) and
they presented the same level of gene variation. The number of migrants
(Nm) indicated that at least 50 individuals per generation migrated
between the three habitats. RAPD-PCR markers revealed that, except for
the primer five, all were polymorphic. Phenetic analysis of the
genotypes showed the presence of two principal clusters corresponding to
: (1) domestic plus extra-domestic and (2) sylvatic. Unique genotypes
were observed in each population. The sylvatic population was the most
polymorphic, showing the largest number of genotypes and low level of
similarity between them. Three mtDNA gene markers were studied by SSCP
analysis. The most frequent haplotype for each marker ranged in
frequency from 60 to 87% and individuals with unique haplotypes varied
from 1 to 5%. Interestingly, the SSCP analysis showed a low level of
polymorphism within populations. The disagreement between the different
molecular markers observed and the hypothesis that L. intermedia could
be participating in the transmission cycle of Leishmania (Viannia)
braziliensis in environments ranging from the interior of human
dwellings to the forest, are discussed.
PMID: 15752185
TITLE: Sand fly species of Sanliurfa province in Turkey.
AUTHORS: S Toprak, N Ozer
AFFILIATION: Biology Department, Harran University, Sanliurfa, Turkey.
REFERENCE: Med Vet Entomol 2005 Mar 19(1):107-10
The species composition and seasonal abundance of sand flies (Diptera:
Phlebotominae) were studied in the years 2000-2002 in the Sanliurfa
region, which is the largest focus of cutaneous leishmaniasis in south-
eastern Turkey. Sixteen species were identified among 29 771 specimens
collected at 17 different sites by light traps, sticky papers and
aspirators. The most common species were Phlebotomus papatasi (Scopoli
) (45.4%), P. perfiliewi Parrot (21.9%), and P. sergenti Parrot (19.4
%). The other species found were P. major Adler & Theodor (3%), P.
neglectus Leger & Pesson (2.2%), P. brevis Theodor & Mesghali (2
%), P. alexandri Sinton (1.9%), P. galilaeus Theodor (1.6%), P.
halepensis Theodor (0.84%), Sergentomyia adleri Theodor (0.78%), S.
dentata Sinton (0.49%), S. minuta Rondani (0.42%), S. theodori Parrot (0
.16%), P. kazeruni Theodor & Mesghali (0.001%) and P. mascitti
Grassi (0.001%) and one unidentified Phlebotomus species. Among these
species P. galilaeus, S. minuta and S. dentata are the first records for
this area. All species showed seasonal fluctuations, with the period of
highest abundance between May and October.
PMID: 15687017
TITLE: Leishmania infantum: soluble proteins released by the parasite exert
differential effects on host immune response.
AUTHORS: R Rosa, O Roos Rodrigues, C Marques, G M Santos-Gomes
AFFILIATION: Unidade de Leishmanioses e Centro de Malária e Outras Doenças
Tropicais, Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova
de Lisboa, Rua da Junqueira 96, 1349-008 Lisboa, Portugal.
REFERENCE: Exp Parasitol 2005 Feb 109(2):106-14
The objective of this study was to analyse the modulatory effect of
proteins released by cultured Leishmania infantum promastigotes on the
cellular immune response of infected susceptible (BALB/c) and more
resistant (C57BL/6) mice strains after 30 and 45 days of infection. One
month after parasite inoculation, L. infantum released protein fractions
(High, Inter, and Low according to molecular weight) stimulated C57BL/6
mice spleen cells to proliferate and to express cytokines. Following
the decrease of parasite load only the Low protein fraction induced a
considerable release of IL-4. In BALB/c mice, specific immune response
to protein fractions was only observed at the higher parasitic level,
with the fraction Inter promoting the production of IL-4 and fractions
High and Low inducing high levels of IL-12. These results point out to a
role of these proteins fractions in the modulation of host immunity,
that depending on the host genetic background and parasite magnitude,
seem to be critical in the control of parasite replication levels, thus
avoiding premature host death.
PMID: 15629360
TITLE: Development of a recombinant Leishmania major strain sensitive to
ganciclovir and 5-fluorocytosine for use as a live vaccine challenge in
clinical trials.
AUTHORS: Noushin Davoudi, Celia A Tate, Corinna Warburton, Angus Murray,
Fereidoun Mahboudi, W Robert McMaster
AFFILIATION: Department of Biotechnology, Pasteur Institute of Tehran, Pasteur
Square, Tehran, Iran.
REFERENCE: Vaccine 2005 Jan 23(9):1170-7
To provide a safer live challenge strain for use in clinical vaccine
trials, a double drug sensitive strain of Leishmania major was derived
using advances in gene targeting technology by stably introducing into
the chromosome a modified HSV-1 thymidine kinase gene (tk), conferring
increased sensitivity to ganciclovir (GCV), and a Saccharomyces
cerevisiae cytosine deaminase gene (cd), conferring sensitivity to 5-
fluorocytosine (5-FC). In vitro studies showed that the homozygous L.
major (tk-cd+/+) promastigotes were killed by either drug alone, and
together the drugs acted synergistically. In vivo infection studies
showed that progressively growing lesions in BALB/c mice, caused by L.
major (tk-cd+/+), were completely cured by 2 weeks of treatment with
either drug alone or in combination. Treated animals showed no signs of
reoccurrence of infection for at least 4 months when the experiments
were terminated.
PMID: 15761608
TITLE: Subclinical form of the American visceral leishmaniasis.
AUTHORS: Mônica Elinor Alves Gama, Jackson MaurÃcio Lopes Costa, Cláudia
Maria Castro Gomes, Carlos Eduardo Pereira Corbett
AFFILIATION: Departamento de Medicina III (Pediatria), Universidade Federal do
Maranhão, Praça Gonçalves Dias 21 ILA, 65020-270 São Luis, MA, Brazil.
mgama at elo.com.br
REFERENCE: Mem Inst Oswaldo Cruz 2004 Dec 99(8):889-93
The subclinical form of visceral leishmaniasis (VL) shows nonspecific
clinical manifestations, with difficulties being frequently met in its
clinical characterization and diagnostic confirmation. Thus, the
objective of the present study was to define the clinical-laboratory
profile of this clinical form. A cohort study was conducted in the state
of Maranhão, Brazil, from January/1998 to December/2000, with monthly
follow-up of 784 children aged 0-5 years. Based on the clinical-
laboratory parameters reported in the literature, four categories were
established, with the children being classified (according to their
clinical-evolutive behavior) as asymptomatic (N = 144), as having the
subclinical form (N = 33) or the acute form (N = 12) or as subjects &
quot;without VL" (N = 595). Multiple discriminant analysis
demonstrated that the combination of fever, hepatomegaly,
hyperglobulinemia, and increased blood sedimentation rate (BSR) can
predict the subclinical form of VL as long as it is not associated with
splenomegaly or leukopenia. Subjects with the subclinical form did not
show prolonged or intermittent evolution or progression to the acute
form of VL. Subclinical cases have a profile differing from the
remaining clinical forms of VL, being best characterized by the
combination of fever, hepatomegaly, hyperglobulinemia, and increased BSR.
PMID: 15761593
TITLE: Study on phlebotomine sand fly (Diptera: Psychodidae) fauna in Belo
Horizonte, state of Minas Gerais, Brazil.
AUTHORS: Carina Margonari de Souza, Jose Eduardo Pessanha, Ricardo Andrade
Barata, Erika Michalsky Monteiro, Daniela Carmargos Costa, Edelberto Santos
Dias
AFFILIATION: Centro de Pesquisas René Rachou-Fiocruz, Av. Augusto de Lima 1715,
30190-002 Belo Horizonte, MG, Brazil.
REFERENCE: Mem Inst Oswaldo Cruz 2004 Dec 99(8):795-803
A study on the phlebotomine sand fly fauna in Belo Horizonte city, state
of Minas Gerais, Brazil, was carried out. From April 2001 to March 2003
, monthly systematic collections were performed in three houses from
each of the nine regions of the city, using CDC light traps for four
consecutive days. The traps were set into the houses and in peridomestic
areas totaling 54 traps. A number of 3871 sand fly specimens of the
genera Lutzomyia and Brumptomyia were collected. Sixty eight percent of
the specimens were L. longipalpis and 16% L. whitmani, insect vectors of
visceral and American cutaneous leishmaniasis, respectively.
Environmental factors such as temperature, humidity, and frequency of
precipitation suggest that the number of insects increases after rainy
periods. During the same period mentioned above, seasonal captures were
carried out in parks and green areas of Belo Horizonte, using Shannon
trap. A total of 579 phlebotomine sand flies were collected from which
398 (68.7%) were females with the predominance of L. whitmani and L.
monticola. Those specimens were used for natural infection examination,
by polymerase chain reaction. No Leishmania DNA was present in any of
the specimens tested.
PMID: 15501546
TITLE: Synthesis and antileishmanial profile of some novel terpenyl
pyrimidines.
AUTHORS: Susmita Pandey, S N Suryawanshi, Suman Gupta, V M L Srivastava
AFFILIATION: Division of Medicinal Chemistry, Central Drug Research Institute,
Lucknow, India.
REFERENCE: Eur J Med Chem 2004 Nov 39(11):969-73
Some novel terpenyl pyrimidine derivatives 2(a-d) and 6(a-b) have been
synthesised from alpha/beta-ionone keteneacetals 1 and 5. The terpenyl
pyrimidine 2e has been synthesised from beta-ionone 3 in two steps in
quantitative yield. The pyrimidine derivatives were screened for in-vivo
antilesihmanial activity. The compounds 2d, 2e, 6a and 6b showed
promising in-vivo antileishmanial activity.
PMID: 15531044
TITLE: Life-long systemic protection in mice vaccinated with L. major and
adenovirus IL-12 vector requires active infection, macrophages and intact lymph
nodes.
AUTHORS: Claudia Raja Gabaglia, Eli E Sercarz, Yaiza Diaz-De-Durana, Mary Hitt,
Frank L Graham, Jack Gauldie, Todd A Braciak
AFFILIATION: Division of Immune Regulation, Torrey Pines Institute for Molecular
Studies, 3550 General Atomics Court, San Diego, CA 92121, USA.
cgabaglia at tpims.org
REFERENCE: Vaccine 2004 Nov 23(2):247-57
Immunization with soluble leishmanial antigen (SLA) in IFA plus Ad5IL-12
vector induced protection confined to the immunized footpad in BALB/c
mice. However, animals that controlled a primary infection with a
Leishmania major challenge in the same immunized footpad, became
resistant to subsequent contralateral rechallenges due to expansion of
IFN-gamma secreting cells. This systemic immunity could be disrupted
either by macrophage depletion during immunization or by lymphadenectomy
after challenge. We show that this procedure does not interfere with
tissue-compartmentalized protection, since lymphadenectomized and
splenectomized animals were resistant to rechallenges performed in the
immunized footpads. Our results indicate that SLA-Ad5IL-12 vector
priming requires macrophages to generate systemic protection.
Furthermore, a previously undescribed lymphoid organ-independent,
protective immune response is contained within the tissue
microenvironment of the immunized/challenged footpad. These results have
important implications for vaccine design against leishmanial and
mycobacterial infections and diseases caused by intracellular pathogens.
PMID: 15509422
TITLE: Identification of Leishmania strains from Jordan.
AUTHORS: E K Saliba, F Pratlong, J P Dedet, N Saleh, S A Khoury, O Y Oumeish, O
Batayneh, R Al-Oran
AFFILIATION: Department of Biotechnology and Genetic Engineering, Philadelphia
University, P.O. Box 1, Amman, 19392, Jordan. salibaek at go.com.jo
REFERENCE: Ann Trop Med Parasitol 2004 Oct 98(7):677-83
The enzymatic profiles of 22 Jordanian Leishmania isolates obtained from
humans, Psammomys obesus and Phlebotomus papatasi were determined using
starch-gel electrophoresis and a 15-enzyme system. Thirteen of the
isolates were typed as L. major and the other nine, all from
Mediterranean or sub-Mediterranean regions, as L. tropica. The two
zymodemes of L. major encountered, MON-26 and MON-103, differed in terms
of purine nucleoside phosphorylase 2. The MON-26 isolates came from the
Jordanian plateau whereas those of MON-103 were only collected from the
Jordan valley. The four zymodemes of L. tropica observed (MON-7, MON-
137, MON-200 and MON-265) were identical for only two of the 15 enzymes
studied (i.e. isocitrate dehydrogenase and glucose phosphate isomerase
), confirming the high level of enzymatic polymorphism of L. tropica. So
far, MON-200 and MON-265 have only been found in Jordan.
PMID: 15776620
TITLE: [Cutaneous leishmaniasis in hospital area: epidemiological and clinical
aspects, about 16 cases]
AUTHORS: S Ndongo, M T Dieng, D Dia, T N Sy, A Leye, M T Diop, B Ndiaye
AFFILIATION: Clinique Médicale I CHU A. Le Dantec, Dakar.
REFERENCE: Dakar Med 2004 49(3):207-10
Cutaneous leishmaniasis, a chronic infectious ulcerative skin disease
caused by a protozoan parasite of the genus Leishmania, is transmitted
by the bite of sandflies. We report 16 cases of cutaneous leishmaniasis
observed in Dakar from 1990 to 2000. The aim of this retrospective study
was to determine the epidemiological and clinical features. Their age
range was 10 to 78 years (mean 41.12 years). The sex ratio was 3. The
most commun presentation was the ulcero-crusted lesions (bouton d'orient
) observed in 56.25% of cases. The other clinical presentation are the
sporotrichoid lesions (25%), the lupoid lesions observed in 12.5% and
the cutaneous diffus leishmaniasis in 12.5%. In all these cases, there
were many lesions. On treatment we observed 87.5% of total remission.
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PMID: 15162428
TITLE: Notch1 expression on T cells is not required for CD4+ T helper
differentiation.
AUTHORS: Fabienne Tacchini-Cottier, Cindy Allenbach, Luc A Otten, Freddy Radtke
AFFILIATION: World Health Organization Immunology Research and Training Centre,
and Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Fabienne.Tacchini-Cottier at ib.unil.ch
REFERENCE: Eur J Immunol 2004 Jun 34(6):1588-96
Notch1 proteins are involved in binary cell fate decisions. To determine
the role of Notch1 in the differentiation of CD4(+) Th1 versus Th2
cells, we have compared T helper polarization in vitro in naive CD4(+) T
cells isolated from mice in which the N1 gene is specifically
inactivated in all mature T cells. Following activation, Notch1-
deficient CD4(+) T cells transcribed and secreted IFN-gamma under Th1
conditions and IL-4 under Th2 conditions at levels similar to that of
control CD4(+) T cells. These results show that Notch1 is dispensable
for the development of Th1 and Th2 phenotypes in vitro. The requirement
for Notch1 in Th1 differentiation in vivo was analyzed following
inoculation of Leishmania major in mice with a T cell-specific
inactivation of the Notch1 gene. Following infection, these mice
controlled parasite growth at the site of infection and healed their
lesions. The mice developed a protective Th1 immune response
characterized by high levels of IFN-gamma mRNA and protein and low
levels of IL-4 mRNA with no IL-4 protein in their lymph node cells.
Taken together, these results indicate that Notch1 is not critically
involved in CD4(+) T helper 1 differentiation and in resolution of
lesions following infection with L. major.
PMID: 15053410
TITLE: Cutaneous leishmaniasis: recognition and treatment.
AUTHORS: William H Markle, Khaldoun Makhoul
AFFILIATION: University of Pittsburgh Medical Center, McKeesport Hospital,
McKeesport, Pennsylvania 15261, USA. marklew at upmc.edu
REFERENCE: Am Fam Physician 2004 Mar 69(6):1455-60
Cutaneous leishmaniasis is a parasitic disease occurring throughout the
Americas from Texas to Argentina, and in the Old World, particularly the
Middle East and North Africa. It is spread by the female sandfly. The
condition is diagnosed every year in travelers, immigrants, and military
personnel. Physicians in the United States must be alert to the
diagnosis of leishmaniasis in travelers returning from endemic areas.
Physicians working for short periods in endemic areas often must make
the diagnosis and should be aware of local disease patterns. When faced
with a possible leishmanial skin lesion, a skin scraping with
microscopic analysis is the best test. Punch biopsies with tissue-
impression smears also can be diagnostic. Needle aspiration of tissue
fluid from the margin of a lesion can yield fluid for culture to isolate
the organism and identify the species. Immunologic tests are being
developed, including a highly sensitive polymerase chain reaction test.
The treatment mainstay is pentavalent antimony (e.g., sodium
stibogluconate). Not all patients require treatment; many lesions heal
spontaneously. Antimonials have a high incidence of reversible adverse
effects. Other medications used for treatment include amphotericin B,
pentamidine isethionate, paromomycin, and antifungals. This disease must
be considered in at-risk patients, and family physicians should know
the basics of diagnosis and where to go for more help.
PMID: 12646217
TITLE: Molecular cloning, biochemical and structural analysis of elongation
factor-1 alpha from Leishmania donovani: comparison with the mammalian
homologue.
AUTHORS: Devki Nandan, Artem Cherkasov, Rafat Sabouti, Taolin Yi, Neil E Reiner
AFFILIATION: Department of Medicine, Division of Infectious Diseases, Faculty of
Medicine, The Research Institute of the Vancouver Hospital and Health Sciences
Center, The University of British Columbia, Vancouver, BC, Canada V5Z 3J5.
dnandan at interchange.ubc.ca
REFERENCE: Biochem Biophys Res Commun 2003 Mar 302(4):646-52
The Src-homology 2 domain containing protein tyrosine phosphatase-1 (SHP
-1) is involved in the pathogenesis of infection with Leishmania.
Recently, we identified elongation factor-1 alpha (EF-1 alpha) from
Leishmania donovani as a SHP-1 binding and activating protein [J. Biol.
Chem. 277 (2002) 50190]. To characterize this apparent Leishmania
virulence factor further, the cDNA encoding L. donovani EF-1 alpha was
cloned and sequenced. Whereas nearly complete sequence conservation was
observed amongst EF-1 alpha proteins from trypanosomatids, the deduced
amino acid sequence of EF-1 alpha of L. donovani when compared to
mammalian EF-1 alpha sequences showed a number of significant changes.
Protein structure modeling-based upon the known crystal structure of EF-
1 alpha for Saccharomyces cerevisiae-identified a hairpin loop present
in mammalian EF-1 alpha and absent from the Leishmania protein which
corresponded to a 12 amino acid deletion. Consistent with these
structural differences, the sub-cellular distributions of L. donovani EF
-1 alpha and host EF-1 alpha were strikingly different. Interestingly,
infection of macrophages with L. donovani caused redistribution of host
as well as pathogen EF-1 alpha. Since EF-1 alpha is essential for
survival, the distinct biochemical and structural properties of
Leishmania EF-1 alpha may provide a novel target for drug development.
PMID: 12384497
TITLE: Leishmania EF-1alpha activates the Src homology 2 domain containing
tyrosine phosphatase SHP-1 leading to macrophage deactivation.
AUTHORS: Devki Nandan, Taolin Yi, Martin Lopez, Crystal Lai, Neil E Reiner
AFFILIATION: Department of Medicine, Division of Infectious Diseases, The
University of British Columbia, Research Institute of the Vancouver Hospital
and Health Sciences Center, Vancouver, British Columbia V5Z 3J5, Canada.
dnandan at interchange.ubc.ca
REFERENCE: J Biol Chem 2002 Dec 277(51):50190-7
The human leishmaniasis are persistent infections of macrophages caused
by protozoa of the genus Leishmania. The chronic nature of these
infections is in part related to induction of macrophage deactivation,
linked to activation of the Src homology 2 domain containing tyrosine
phosphatase-1 (SHP-1) in infected cells. To investigate the mechanism of
SHP-1 activation, lysates of Leishmania donovani promastigotes were
subjected to SHP-1 affinity chromatography and proteins bound to the
matrix were sequenced by mass spectrometry. This resulted in the
identification of Leishmania elongation factor-1alpha (EF-1alpha) as a
SHP-1-binding protein. Purified Leishmania EF-1alpha, but not host cell
EF-1alpha, bound directly to SHP-1 in vitro leading to its activation.
Three independent lines of evidence indicated that Leishmania EF-1alpha
may be exported from the phagosome thereby enabling targeting of host
SHP-1. First, cytosolic fractions prepared from macrophages infected
with [(35)S]methionine-labeled organisms contained Leishmania EF-1alpha
. Second, confocal, fluorescence microscopy using Leishmania-specific
antisera detected Leishmania EF-1alpha in the cytosol of infected cells
. Third, co-immunoprecipitation showed that Leishmania EF-1alpha was
associated with SHP-1 in vivo in infected cells. Finally, introduction
of purified Leishmania EF-1alpha, but not the corresponding host protein
into macrophages activated SHP-1 and blocked the induction of inducible
nitric-oxide synthase expression in response to interferon-gamma. Thus
, Leishmania EF-1alpha is identified as a novel SHP-1-binding and
activating protein that recapitulates the deactivated phenotype of
infected macrophages.
PMID: 11745335
TITLE: Role of host phosphotyrosine phosphatase SHP-1 in the development of
murine leishmaniasis.
AUTHORS: G Forget, K A Siminovitch, S Brochu, S Rivest, D Radzioch, M Olivier
AFFILIATION: Centre de Recherche en Infectiologie CHUQ, Université Laval,
Ste-Foy, Québec, Canada.
REFERENCE: Eur J Immunol 2001 Nov 31(11):3185-96
Activation of host phosphotyrosine phosphatase SHP-1 by Leishmania and
its subsequent impact on tyrosine phosphorylation-based signaling
cascades were shown to represent an important mechanism whereby this
pathogen may alter host cell functions. Herein, we report that
Leishmania-induced macrophage SHP-1 activity is necessary for its
survival within phagocytes through the attenuation of nitric oxide-
dependent and -independent microbicidal mechanisms. In vivo, Leishmania
major infection, which footpad inflammation is mostly undetectable in
SHP-1-deficient viable motheaten mice, was accompanied by increased
inducible nitric oxide synthase and activation of neutrophils. These
enhanced cellular activities were paralleled by a marked activation of
signaling events usually negatively regulated by SHP-1. Overall, this
study firmly establishes that modulation of the signaling terminator SHP
-1 by Leishmania is essential for its installment and propagation.
PMID: 11544330
TITLE: Sodium stibogluconate is a potent inhibitor of protein tyrosine
phosphatases and augments cytokine responses in hemopoietic cell lines.
AUTHORS: M K Pathak, T Yi
AFFILIATION: Department of Cancer Biology, Lerner Research Institute, Cleveland
Clinic Foundation, Cleveland, OH 44195, USA.
REFERENCE: J Immunol 2001 Sep 167(6):3391-7
Using in vitro protein tyrosine phosphatase (PTPase) assays, we found
that sodium stibogluconate, a drug used in treatment of leishmaniasis,
is a potent inhibitor of PTPases Src homology PTPase1 (SHP-1), SHP-2,
and PTP1B but not the dual-specificity phosphatase mitogen-activated
protein kinase phosphatase 1. Sodium stibogluconate inhibited 99% of SHP
-1 activity at 10 micrograms/ml, a therapeutic concentration of the drug
for leishmaniasis. Similar degrees of inhibition of SHP-2 and PTP1B
required 100 micrograms/ml sodium stibogluconate, demonstrating
differential sensitivities of PTPases to the inhibitor. The drug
appeared to target the SHP-1 domain because it showed similar in vitro
inhibition of SHP-1 and a mutant protein containing the SHP-1 PTPase
domain alone. Moreover, it forms a stable complex with the PTPase: in
vitro inhibition of SHP-1 by the drug was not removed by a washing
process effective in relieving the inhibition of SHP-1 by the reversible
inhibitor suramin. The inhibition of cellular PTPases by the drug was
suggested by its rapid induction of tyrosine phosphorylation of cellular
proteins in Baf3 cells and its augmentation of IL-3-induced Janus
family kinase 2/Stat5 tyrosine phosphorylation and proliferation of Baf3
cells. The augmentation of the opposite effects of GM-CSF and IFN-alpha
on TF-1 cell growth by the drug indicated its broad activities in the
signaling of various cytokines. These data represent the first evidence
that sodium stibogluconate inhibits PTPases and augments cytokine
responses. Our results provide novel insights into the pharmacological
effects of the drug and suggest potential new therapeutic applications.
PMID: 11207597
TITLE: Macrophage subsets harbouring Leishmania donovani in spleens of infected
BALB/c mice: localization and characterization.
AUTHORS: T Lang, P Avé, M Huerre, G Milon, J C Antoine
AFFILIATION: Département de Physiopathologie, Institut Pasteur, Paris, France.
tlang at pasteur.fr
REFERENCE: Cell Microbiol 2000 Oct 2(5):415-30
The purpose of the current study was to characterize parasite-containing
cells located in spleens of BALB/c mice infected with Leishmania
donovani. In particular, expression of MHC class II molecules by these
cells was examined to determine whether they could potentially act as
cells capable of immunostimulating Leishmania-reactive CD4+ T
lymphocytes. To this end, an immunohistological analysis of spleens
taken at various time points after infection was undertaken. Using this
approach, we observed, in the red pulp, the formation of small cellular
infliltrates containing heavily infected macrophages that could be
stained with the monoclonal antibodies MOMA-2 and FA/11. All of them
expressed high levels of MHC class II molecules. Parasites were also
detected in the white pulp, especially in MOMA-2+, FA/11+ and MHC class
II+ macrophages of the periarteriolar lymphocyte sheath and in MOMA-2+
marginal zone macrophages. Infected cells were further characterized by
fluorescence microscopy after their enrichment by adherence. All
infected mononuclear cells recovered by this procedure could be stained
with MOMA-2 and FA/11 and thus very probably belonged to the mononuclear
phagocyte lineage. Furthermore, all of them strongly expressed both MHC
class II as well as H-2M molecules, regardless of the time points after
infection. Analysis of the parasitophorous vacuoles (PV) by confocal
microscopy showed that these compartments were surrounded by a membrane
enriched in lysosomal glycoproteins lamp-1 and lamp-2, in macrosialin (a
membrane protein of prelysosomes recognized by FA/11) and in MOMA-2
antigen. About 80% of the PV also had MHC class II and H-2M molecules on
their membrane. Altogether, these data indicate that in the spleens of
L. donovani-infected mice, a high percentage of amastigotes are located
in macrophages expressing MHC class II molecules and that they live in
PV exhibiting properties similar to those of PV detected in mouse bone
marrow-derived macrophages exposed to a low dose of interferon gamma (
IFN-gamma) and infected in vitro.
PMID: 7983173
TITLE: Leishmania donovani-infected macrophages: characterization of the
parasitophorous vacuole and potential role of this organelle in antigen
presentation.
AUTHORS: T Lang, R Hellio, P M Kaye, J C Antoine
AFFILIATION: Département de Physiopathologie Expérimentale, Institut Pasteur,
Paris, France.
REFERENCE: J Cell Sci 1994 Aug 107 ( Pt 8)():2137-50
Leishmania donovani amastigotes, the etiological agents of visceral
leishmaniasis, are obligate intracellular parasites residing in membrane
-bound compartments of macrophages called parasitophorous vacuoles (PV
). The study of these organelles is of paramount importance to
understanding how these parasites resist the microbicidal mechanisms of
macrophages and how they escape the immune response of their hosts.
Confocal microscopy of mouse bone marrow-derived macrophages infected
with L. donovani amastigotes and stained for various prelysosomal/
lysosomal markers and for major histocompatibility complex (MHC)
molecules was used to define PV with respect to the endocytic
compartments of the host cells and to address the issue of their
potential role in antigen processing and presentation. Forty-eight hours
after infection, many PV contained cathepsins B, D, H and L and they
were all surrounded by a membrane enriched for the lysosomal
glycoprotein lgp120/lamp 1 but apparently devoid of the cation-
independent mannose 6-phosphate receptor, a membrane protein generally
absent from the lysosomes. These data suggested that PV acquire within
48 hours the characteristics of a lysosomal compartment. However, both
macrosialin and the GTP-binding protein rab7p (specific markers of the
prelysosomal compartment) were found to be highly expressed in/on PV
membrane. Thus, at this stage, PV appear to exhibit both lysosomal and
prelysosomal features. Infected macrophages activated with IFN-gamma
before or after infection showed PV strongly stained for MHC class II
molecules but not for MHC class I molecules. This suggests that, if
infected macrophages can act as antigen-presenting cells for class I-
restricted CD8+ T lymphocytes, Leishmania antigens must exit the PV. MHC
class II molecules reached the PV progressively, indicating that they
were not plasma membrane-bound molecules trapped during internalization
of the parasites. The redistribution of class II observed in infected
cells did not alter their quantitative expression on the plasma membrane
at least during the first 48 hours following the phagocytosis of the
parasites. The invariant chains, which are transiently associated with
class II molecules during their intracellular transport and which mask
their peptide-binding sites, did not reach PV or were rapidly degraded
in these sites, suggesting that PV-associated class II are able to bind
peptides. This last assumption is strengthened by the fact that class II
located in PV could bind conformational antibodies that preferentially
recognize class II with tightly associated peptides.(ABSTRACT TRUNCATED
AT 400 WORDS)
REQUEST: [ leishmania ]
(35 articles match this request. 22 articles matching other requests removed)
PMID: 15777918
TITLE: Ploidy changes associated with disruption of two adjacent genes on
Leishmania major chromosome 1.
AUTHORS: Santiago MartÃnez-Calvillo, Kenneth Stuart, Peter J Myler
AFFILIATION: Seattle Biomedical Research Institute, 307 Westlake Ave. N.,
Seattle, WA 98109-5219, USA.
REFERENCE: Int J Parasitol 2005 Apr 35(4):419-29
Leishmania major Friedlin (LmjF) is a kinetoplastid protozoan whose
genomic sequence has been recently elucidated. About 60% of the
identified genes do not have a known function, and many are
trypanosomatid-specific. Here we characterise two adjacent genes from
LmjF chromosome 1 (chr1): LmjF01.0750, which encodes a predicted protein
with a serine/threonine protein kinase motif and LmjF01.0760, which
encodes a product with no similarity to other known proteins.
Orthologues of both genes are present in Trypanosoma cruzi, but neither
occur in Trypanosoma brucei. We have mapped polyadenylation and spliced-
leader acceptor sites for both genes, and show that they differ between
Leishmania species. Attempts to generate null mutants of LmjF01.0750 by
homologous recombination were unsuccessful and led to the apparent
triploidy of the entire genome, suggesting that it is an essential gene
. Interestingly, at least two copies of LmjF01.0750 are required for
cell survival. Further evidence of genome plasticity in Leishmania was
provided by changes in chr1 copy number that occurred during in vitro
growth of wild-type LmjF promastigotes and following replacement of a
single copy of LmjF01.0760.
PMID: 15491798
TITLE: Can heterologous gene expression shed (a torch) light on protein
function?
AUTHORS: Pascal Dubessay, Michel Pagès, Frédéric Delbac, Patrick Bastien,
Christian Vivares, Christine Blaineau
REFERENCE: Trends Biotechnol 2004 Nov 22(11):557-9
PMID: 15765593
TITLE: Immunoblotting analyses using two-dimensional gel electrophoresis of
Trypanosoma cruzi excreted-secreted antigens.
AUTHORS: Adriano Gomes Silva, Elisangela Paula Silveira-Lacerda, Jair Pereira
Cunha-Júnior, Maria Aparecida de Souza, Silvio Favoreto Junior
AFFILIATION: Laboratório de Imunologia do Instituto de Ciências Biomédicas da
Universidade Federal de Uberlândia, Uberlândia, MG, Brasil.
REFERENCE: Rev Soc Bras Med Trop 2004 Nov-Dec 37(6):454-9
Trypanosoma cruzi trypomastigotes excrete-secrete a complex mixture of
antigenic molecules. This antigenic mixture denominated trypomastigote
excreted-secreted antigens contains a 150-160 kDa band that shows
excellent performance in Chagas' disease diagnosis by immunoblotting.
The present study partially characterized by two-dimensional gel
electrophoresis the immunoreactivity against the 150-160 kDa protein
using sera samples from chagasic patients in different phases of the
disease. Trypomastigote excreted-secreted antigen preparations were
subjected to high-resolution two-dimensional (2D) gel electrophoresis
followed by immunoblotting with sera from chagasic and non-chagasic
patients. The 150-160 kDa protein presented four isoforms with
isoelectric focusing ranging from 6.2 to 6.7. The four isoforms were
recognized by IgM from acute phase and IgG from chronic phase sera of
chagasic patients. The 150-160 kDa isoform with IF of approximately 6.4
became the immunodominant spot with the progression of the disease. No
cross-reactivity was observed with non-chagasic or patients infected
with Leishmania sp. In this study we provide basic knowledge that
supports the validation of trypomastigote excreted-secreted antigens for
serological diagnosis of Chagas' disease.
PMID: 15765605
TITLE: [A comparison of two antigens for Montenegro skin test]
AUTHORS: Héctor Dardo Romero, AluÃzio Prata, Mário León Silva-Vergara,
Luciana de Almeida Silva
AFFILIATION: Disciplina de Doenças Infecciosas e Parasitárias da Faculdade de
Medicina do Triângulo Mineiro, Uberaba, MG.
REFERENCE: Rev Soc Bras Med Trop 2004 Nov-Dec 37(6):508-9
Intradermal reactions were performed in 399 individuals by using,
simultaneously, the antigen produced by both the Universidade Federal de
Minas Gerais and Fundação Instituto Oswaldo Cruz. Each of these
antigens was manufactured with promastigotes of Leishmania (L)
amazonensis (IFLA/BR/67/PH8). The Fundação Oswaldo Cruz antigen caused
a larger number of positive reactions. Discordant reactions occurred in
22% of the individuals.
PMID: 15770804
TITLE: [Antiparasitic activities of Senegalese Annonaceae used in traditional
medicine]
AUTHORS: D Fall, M Badiane, D Ba, P Loiseau, C Bories, C Gleye, A Laurens, R
Hocquemiller
AFFILIATION: Laboratoire de chimie organique et thérapeutique, Faculté de
Médecine, Pharmacie et Odonto-stomatologie, Dakar, Sénégal.
REFERENCE: Dakar Med 2003 48(2):112-6
Annonaceae is a large family of plants widely used in alimentation and
traditional medicine. The interest of their study is raised up by the
presence of biologically active substances among that the acetogenins
which are specific to them. In Senegal, three species are widely used in
traditional medicine for various indications and particularly in
parasitic diseases: Annona senegalensis, Uvaria chamae and Xylopia
aethiopica. The study of antiparasitical extracts from various organs
showed an interesting activity of the fruits and leaves of Xylopia
aethiopica on Leishmania donovani, the stem barks and roots of Uvaria
chamae on Trypanosomia brucei and the roots of Annona senegalensis on
the chloroquino-resistant strain of Plasmodium falciparum. Bioguided
fractionation of the active extracts led to isolate Annonaceous
acetogenins. Therefore, thirteen acetogenins, from the roots of Uvaria
chamae and Annona senegalensis, were identified. The presence of
acetogenins, substances with antiparasitical activity, could partly
explain the biological proprieties of these various drugs.
********************************************************************************************************************
The following references are revised files and are brought to you in accordance
to license agreement with the NLM.
********************************************************************************************************************
PMID: 12646218
TITLE: Role of protein kinase C alpha for uptake of unopsonized prey and
phagosomal maturation in macrophages.
AUTHORS: A Holm, K Tejle, T Gunnarsson, K-E Magnusson, A Descoteaux, B
Rasmusson
AFFILIATION: Division of Medical Microbiology, Department of Molecular and
Clinical Medicine, Faculty of Health Sciences, Linköping University, S-581 85
Linköping, Sweden. asa.holm at imk.lu.se
REFERENCE: Biochem Biophys Res Commun 2003 Mar 302(4):653-8
Protein kinase C alpha (PKC alpha) participates in F-actin remodeling
during phagocytosis and phagosomal maturation in macrophages. Leishmania
donovani promastigotes, which inhibit phagosomal maturation, cause
accumulation of periphagosomal F-actin instead of the disassembly
observed around other prey [Cell. Microbiol. 7 (2001) 439]. This
accumulation is induced by promastigote lipophosphoglycan (LPG), which
has several effects on macrophages including inhibition of PKC alpha. To
investigate a possible connection between PKC alpha and LPG's effects
on actin dynamics, we utilized RAW264.7 macrophages overexpressing
dominant-negative PCK alpha (DN PKC alpha). We found increased cortical
F-actin and decreased phagocytic capacity, as well as defective
periphagosomal F-actin breakdown and inhibited phagosomal maturation in
the DN PKC alpha-overexpressing cells, effects similar to those seen in
controls subjected to LPG-coated prey. The results indicate that PKC
alpha is involved in F-actin turnover in macrophages and that PKC alpha-
dependent breakdown of periphagosomal F-actin is required for phagosomal
maturation, and endorse the hypothesis that intracellular survival of L
. donovani involves inhibition of PKC alpha by LPG.
PMID: 11437830
TITLE: Leishmania donovani lipophosphoglycan causes periphagosomal actin
accumulation: correlation with impaired translocation of PKCalpha and defective
phagosome maturation.
AUTHORS: Holm A, K Tejle, K E Magnusson, A Descoteaux, B Rasmusson
AFFILIATION: Division of Medical Microbiology, Department of Health and
Environment, Faculty of Health Sciences, Linköping University, S-581 85
Linköping, Sweden. asaholm at hem.passagen.se
REFERENCE: Cell Microbiol 2001 Jul 3(7):439-47
Lipophosphoglycan (LPG) is the major surface glycoconjugate of
Leishmania donovani promastigotes. The repeating disaccharide-phosphate
units of LPG are crucial for promastigote survival inside macrophages
and establishment of infection. LPG has a number of effects on the host
cell, including inhibition of PKC activity, inhibition of nitric oxide
production and altered expression of cytokines. LPG also inhibits
phagosomal maturation, a process requiring depolymerization of
periphagosomal F-actin. In the present study, we have characterized the
dynamics of F-actin during the phagocytosis of L. donovani promastigotes
in J774 macrophages. We observed that F-actin accumulated progressively
around phagosomes containing wild-type L. donovani promastigotes during
the first hour of phagocytosis. Using LPG-defective mutants and yeast
particles coated with purified LPG, we obtained evidence that this
effect could be attributed to the repeating units of LPG. LPG also
disturbed cortical actin turnover during phagocytosis. The LPG-dependent
accumulation of periphagosomal F-actin correlated with an impaired
recruitment of the lysosomal marker LAMP1 and PKCalpha to the phagosome
. Accumulation of periphagosomal F-actin during phagocytosis of L.
donovani promastigotes may contribute to the inhibition of phagosomal
maturation by physically preventing vesicular trafficking to and from
the phagosome.
PMID: 11067875
TITLE: Legionella pneumophila replication vacuoles mature into acidic, endocytic
organelles.
AUTHORS: S Sturgill-Koszycki, M S Swanson
AFFILIATION: Department of Microbiology and Immunology, University of Michigan,
Ann Arbor, Michigan 48109, USA.
REFERENCE: J Exp Med 2000 Nov 192(9):1261-72
After ingestion by macrophages, Legionella pneumophila inhibits
acidification and maturation of its phagosome. After a 6-10-h lag period
, the bacteria replicate for 10-14 h until macrophage lysis releases
dozens of progeny. To examine whether the growth phase of intracellular
L. pneumophila determines the fate of its phagosome, interactions
between the endosomal network and pathogen vacuoles were analyzed
throughout the primary infection period. Surprisingly, as L. pneumophila
replicated exponentially, a significant proportion of the vacuoles
acquired lysosomal characteristics. By 18 h, 70% contained lysosomal-
associated membrane protein 1 (LAMP-1) and 40% contained cathepsin D; 50
% of the vacuoles could be labeled by endocytosis, and the pH of this
population of vacuoles averaged 5.6. Moreover, L. pneumophila appeared
to survive and replicate within lysosomal compartments: vacuoles
harboring more than five bacteria also contained LAMP-1, inhibition of
vacuole acidification and maturation by bafilomycin A1 inhibited
bacterial replication, bacteria within endosomal vacuoles responded to a
metabolic inducer by expressing a gfp reporter gene, and replicating
bacteria obtained from macrophages, but not broth, were acid resistant.
Understanding how L. pneumophila first evades and then exploits the
endosomal pathway to replicate within macrophages may reveal the
mechanisms governing phagosome maturation, a process also manipulated by
Mycobacteria, Leishmania, and Coxiella.
PMID: 10984443
TITLE: Rab5 regulates the kiss and run fusion between phagosomes and endosomes
and the acquisition of phagosome leishmanicidal properties in RAW 264.7
macrophages.
AUTHORS: S Duclos, R Diez, J Garin, B Papadopoulou, A Descoteaux, H Stenmark, M
Desjardins
AFFILIATION: Département de pathologie et biologie cellulaire, Université de
Montréal, C.P. 6128, Succ. Centre ville, Montréal, QC, Canada, H3C 3J7.
REFERENCE: J Cell Sci 2000 Oct 113 Pt 19():3531-41
Phagolysosome biogenesis is essential for the killing and degradation of
intracellular pathogens. It involves the fusion of phagosomes with
various endocytic organelles, a process known to be regulated in part by
Rab proteins. We generated RAW 264.7 macrophages expressing an active
mutant of Rab5 (Rab5(Q79L)) to determine the role of Rab5 in
phagocytosis and phagolysosome biogenesis. Our results indicate that
Rab5 stimulates phagocytosis of latex beads but not Fc or C3 receptor-
mediated phagocytosis. Rab5 also acts to restrict the complete fusion of
phagosomes with endosomes, a phenomenon allowing exchange of solutes
from the two compartments without complete intermixing of their membrane
(kiss and run). In Rab5(Q79L)-expressing macrophages, uncontrolled
fusion events occurred, leading to the appearance of giant phagosomes.
These phagosomes could initiate their maturation and acquire LAMP1, but
failed to generate the microbicidal conditions needed to kill
intracellular parasites. These results identify Rab5 as a key molecule
regulating phagosome-endosome fusion and as an essential component in
the innate ability of macrophages to restrict the growth of
intracellular parasites.
PMID: 10556830
TITLE: Leishmania-induced increases in activation of macrophage SHP-1 tyrosine
phosphatase are associated with impaired IFN-gamma-triggered JAK2 activation.
AUTHORS: J Blanchette, N Racette, R Faure, K A Siminovitch, M Olivier
AFFILIATION: Centre de Recherche en Infectiologie Laval University Medical
Research Center, Université Laval, Ste-Foy, Canada.
REFERENCE: Eur J Immunol 1999 Nov 29(11):3737-44
Leishmania-induced macrophage (Mphi) dysfunctions have been correlated
with altered signaling events. Recent findings from our laboratory
suggest that modulation of host protein tyrosine phosphatase (PTP)
following Leishmania infection could lead to these Mphi defects. To
address this issue, Mphi PTP activity and IFN-gamma-inducible signaling
events were evaluated in Leishmania donovani (Ld)-infected cells. We
observed that Ld promastigotes can rapidly trigger host PTP activity
simultaneously with dephosphorylation of Mphi protein tyrosyl residues
and inhibition of protein tyrosine kinase (PTK). Our results further
revealed that Mphi SHP-1 PTP was rapidly activated by the infection.
This Ld-evoked signaling alteration was reflected by absence of IFN-
gamma-induced intracellular phosphorylation. IFN-gamma-inducible JAK2
PTK phosphorylation was also markedly diminished in Ld-infected cells.
We also observed that co-immunoprecipitation of JAK2 with SHP-1 was
considerably higher in infected as compared to uninfected cells.
Altogether, these results suggest that SHP-1-mediated JAK2
dephosphorylation triggered by Leishmania is partly responsible for
abnormal Mphi IFN-gamma signaling and represent an important mechanism
supporting persistent parasitic infection.
PMID: 10417174
TITLE: Activation of phosphotyrosine phosphatase activity attenuates
mitogen-activated protein kinase signaling and inhibits c-FOS and nitric oxide
synthase expression in macrophages infected with Leishmania donovani.
AUTHORS: D Nandan, R Lo, N E Reiner
AFFILIATION: Department of Medicine (Division of Infectious Diseases), Faculty
of Medicine, University of British Columbia, Vancouver, British Columbia,
Canada V5Z 3J5.
REFERENCE: Infect Immun 1999 Aug 67(8):4055-63
Intracellular protozoan parasites of the genus Leishmania antagonize
host defense mechanisms by interfering with cell signaling in
macrophages. In this report, the impact of Leishmania donovani on
mitogen-activated protein (MAP) kinases and nitric oxide synthase (NOS)
expression in the macrophage cell line RAW 264 was investigated.
Overnight infection of cells with leishmania led to a significant
decrease in phorbol-12-myristate-13-acetate (PMA)-stimulated MAP kinase
activity and inhibited PMA-induced phosphorylation of the MAP kinase
substrate and transcription factor Elk-1. Simultaneously, leishmania
infection markedly attenuated the induction of c-FOS and inducible
nitric oxide synthase (iNOS) expression in response to PMA and gamma
interferon (IFN-gamma), respectively. These effects correlated with
decreased phosphorylation of p44 and p42 MAP kinases on tyrosine
residues. Consistent with the latter finding, lysates prepared from
leishmania-infected cells contained an activity that dephosphorylated
MAP kinase in vitro, suggesting the possibility of a phosphatase acting
in vivo. Attenuation of both MAP kinase activity and c-FOS and iNOS
expression was reversed by treatment of macrophages with sodium
orthovanadate prior to infection. It was also found that the specific
activity of the Src homology 2 domain containing tyrosine phosphatase (
SHP-1) toward MAP kinase was markedly increased in leishmania-infected
cells. These findings indicate that infection with L. donovani
attenuates MAP kinase signaling and c-FOS and iNOS expression in
macrophages by activating cellular phosphotyrosine phosphatases. This
may represent a novel mechanism of macrophage deactivation during
intracellular infection.
PMID: 11207538
TITLE: Impaired recruitment of the small GTPase rab7 correlates with the
inhibition of phagosome maturation by Leishmania donovani promastigotes.
AUTHORS: S Scianimanico, M Desrosiers, J F Dermine, S Méresse, A Descoteaux, M
Desjardins
AFFILIATION: Département de pathologie et biologie cellulaire, Université de
Montréal, Québec, Canada.
REFERENCE: Cell Microbiol 1999 Jul 1(1):19-32
We have shown recently that one of the survival strategies used by
Leishmania donovani promastigotes during the establishment of infection
in macrophages consists in inhibiting phagosome-endosome fusion. This
inhibition requires the expression of lipophosphoglycan (LPG), the
predominant surface glycoconjugate of promastigotes, as parasites
expressing truncated forms of LPG reside in phagosomes that fuse
extensively with endocytic organelles. In the present study, we
developed a single-organelle fluorescence analysis approach to study and
analyse the intracellular trafficking of 'fusogenic' and 'low-fusogenic
' phagosomes induced by an LPG repeating unit-defective mutant (Ipg2 KO
) or by wild-type L. donovani promastigotes respectively. The results
obtained indicate that phagosomes containing mutant parasites fuse
extensively with endocytic organelles and transform into phagolysosomes
by losing the early endosome markers EEA1 and transferrin receptor, and
acquiring the late endocytic and lysosomal markers rab7 and LAMP1. In
contrast, a majority of 'low-fusogenic' phagosomes containing wild-type
L. donovani promastigotes do not acquire rab7, wheres they acquire LAMP1
with slower kinetics. These results suggest that L. donovani parasites
use LPG to restrict phagosome-endosome fusion at the onset of infection
in order to prevent phagosome maturation. This is likely to permit the
transformation of hydrolase-sensitive promastigotes into hydrolase-
resistant amastigotes within a hospitable vacuole not displaying the
harsh environment of phagolysosomes.
PMID: 8303277
TITLE: Lack of acidification in Mycobacterium phagosomes produced by exclusion
of the vesicular proton-ATPase.
AUTHORS: S Sturgill-Koszycki, P H Schlesinger, P Chakraborty, P L Haddix, H L
Collins, A K Fok, R D Allen, S L Gluck, J Heuser, D G Russell
AFFILIATION: Department of Molecular Microbiology, Washington University Medical
Center, St. Louis, MO 63110.
REFERENCE: Science 1994 Feb 263(5147):678-81
The success of Mycobacterium species as pathogens depends on their
ability to maintain an infection inside the phagocytic vacuole of the
macrophage. Although the bacteria are reported to modulate maturation of
their intracellular vacuoles, the nature of such modifications is
unknown. In this study, vacuoles formed around Mycobacterium avium
failed to acidify below pH 6.3 to 6.5. Immunoelectron microscopy of
infected macrophages and immunoblotting of isolated phagosomes showed
that Mycobacterium vacuoles acquire the lysosomal membrane protein LAMP-
1, but not the vesicular proton-adenosine triphosphatase (ATPase)
responsible for phagosomal acidification. This suggests either a
selective inhibition of fusion with proton-ATPase-containing vesicles or
a rapid removal of the complex from Mycobacterium phagosomes.
REQUEST: [ sand fly ]
(2 articles match this request. 2 articles matching other requests removed)
REQUEST: [ sandfly ]
(2 articles match this request. 2 articles matching other requests removed)
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