[leish-l] Fwd: Articles found by RefScout 25/05/05 - 21/2005
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REQUEST: [ leishmaniasis ]
(22 articles match this request)
PMID: 15898000
TITLE: A Heterologous Prime-Boost Vaccination Regimen Using ORFF DNA and
Recombinant ORFF Protein Confers Protective Immunity against Experimental
Visceral Leishmaniasis.
AUTHORS: Poonam Tewary, Manju Jain, Mayurbhai H Sahani, Shailendra Saxena,
Rentala Madhubala
AFFILIATION: School of Life Sciences, Jawaharlal Nehru University, New Delhi,
India.
REFERENCE: J Infect Dis 2005 Jun 191(12):2130-7
Objective. We describe the effectiveness of a prime-boost vaccination
regimen using the open-reading frame (ORFF) gene from the LD1 locus of
Leishmania donovani.Methods. A group of BALB/c mice was immunized with
the plasmid carrying the gene for ORFF (F/pcDNA 3.1) and given a booster
dose of either the same DNA vaccine or a vaccine with a recombinant
ORFF (rORFF) protein. Another group of BALB/c mice was immunized and
given a booster dose of the rORFF protein vaccine. The protective
efficacies of these vaccine formulations were compared after challenge
with L. donovani stationary-phase promastigotes.Results. Mice given the
prime-boost vaccination regimen had an enhanced reduction in parasite
load (75%-80%), compared with that in mice given only the rORFF protein
vaccine (45%-60%). However, the protective response induced in the prime
-boost group was not more than that elicited in the DNA vaccine group.
Immunization with only the rORFF protein vaccine did not induce the
typical T helper response, whereas priming with the DNA vaccine resulted
in enhanced production of immunoglobulin G2a and interferon- gamma .
Furthermore, priming with the DNA vaccine also led to enhanced
proliferation of splenocytes, suggesting subsequent expansion of antigen
-specific T cells.Conclusions. The heterologous prime-boost vaccination
strategy may be utilized for visceral leishmaniasis.
PMID: 15908422
TITLE: CD4+ T Cells Play a Dominant Role in Protection against New World
Leishmaniasis Induced by Vaccination with the P-4 Amastigote Antigen.
AUTHORS: Sujata Kar, Christine Metz, Diane McMahon-Pratt
AFFILIATION: Department of Epidemiology and Public Health, Yale University
School of Medicine, 60 College Street, New Haven, CT 06520-8034.
diane.mcmahon-pratt at yale.edu.
REFERENCE: Infect Immun 2005 Jun 73(6):3823-7
Immunodepletion studies of P-4-vaccinated mice indicate that CD4(+) and
not CD8(+) T cells are critical for protection against Leishmania
pifanoi (Leishmania mexicana complex). Although a moderate CD8(+) T-cell
response is elicited by vaccination, CD4(+) T cells are the dominant
responding population in vitro and at the cutaneous site of infection.
These protective T cells produce gamma interferon (IFN-gamma),
macrophage migration inhibitory factor (MIF), and tumor necrosis factor/
lymphotoxin (TNF/LT), each of which significantly contributed to
intracellular parasite destruction in vitro. These results indicate that
a singular CD4(+) T-cell response (IFN-gamma, MIF, and/or LT/TNF) can
provide protection against New World cutaneous leishmaniasis.
PMID: 15909255
TITLE: Successful treatment with miltefosine of disseminated cutaneous
leishmaniasis in a severely immunocompromised patient infected with HIV-1.
AUTHORS: Christine Schraner, Barbara Hasse, Urs Hasse, Doris Baumann, Anja Faeh,
Günther Burg, Felix Grimm, Alex Mathis, Rainer Weber, Huldrych F Günthard
AFFILIATION: Division of Infectious Diseases and Hospital Epidemiology,
University Hospital Zurich, Zurich, Switzerland.
REFERENCE: Clin Infect Dis 2005 Jun 40(12):e120-4
We describe here a case of disseminated cutaneous leishmaniasis due to
Leishmania major in a severely immunocompromised patient from Burkino
Faso, Africa, who is infected with human immunodeficiency virus-1. The
skin lesions failed to respond to full treatment courses of amphotericin
B, sodium stibogluconate, and liposomal amphotericin B but were
successfully treated with miltefosine, an alkylphosphocholine analogue.
PMID: 15905558
TITLE: CD4+CD25+ Regulatory T Cells Restrain Pathogenic Responses during
Leishmania amazonensis Infection.
AUTHORS: Jiaxiang Ji, Joseph Masterson, Jiaren Sun, Lynn Soong
AFFILIATION: Departments of Microbiology and Immunology and Pathology, Institute
for Human Infections and Immunity, University of Texas Medical Branch,
Galveston, TX 77555.
REFERENCE: J Immunol 2005 Jun 174(11):7147-53
Although activation of CD4(+) T cells mediates pathogenesis in
Leishmania amazonensis (La)-infected mice, these susceptible mice do not
develop a polarized Th2 response, suggesting a unique mechanism of
disease susceptibility. To understand how Th cell activities are
regulated, we examined the frequency and phenotypes of regulatory T (
Treg) cells. At 1-3 wk of infection, relatively high percentages of CD4
(+)CD25(+)CD86(+) T cells, as well as high levels of FoxP3, TGF-beta1,
and IL-10RI transcripts, were detected in the skin and draining lymph
nodes, indicating local accumulation of Treg cells. Lesion-derived, IL-
10-producing CD4(+)CD25(+) cells effectively suppressed proliferation
and cytokine (IL-2 and IFN-gamma) production of CD4(+)CD25(-) effector
cells. Adoptive transfer of lesion-derived CD4(+)CD25(+) cells to
syngeneic, naive C57BL/6 mice before infection significantly reduced
disease development. To further validate the beneficial role of Treg
cells in La infection, we adoptively transferred CD25(+) T cell-depleted
splenocytes (derived from naive mice) into RAG1(-/-) mice. This
transfer rendered RAG1(-/-) mice more susceptible to La infection than
the mice receiving control splenocytes. The beneficial effect of Treg
cells was transitory and correlated with decreased activation of IFN-
gamma-producing effector T cells. This study uncovers an intriguing role
of Treg cells in restraining pathogenic responses during nonhealing
Leishmania infection and emphasizes a balance between Treg and Th1-like
effector cells in determining the outcome of New World cutaneous
leishmaniasis.
PMID: 15905560
TITLE: Kinetoplastid Membrane Protein-11 DNA Vaccination Induces Complete
Protection against Both Pentavalent Antimonial-Sensitive and -Resistant Strains
of Leishmania donovani That Correlates with Inducible Nitric Oxide Synthase
Activity and IL-4 Generation: Evidence for Mixed Th1- and Th2-Like Responses in
Visceral Leishmaniasis.
AUTHORS: Rajatava Basu, Suniti Bhaumik, Jayati Mookerjee Basu, Kshudiram Naskar,
Tripti De, Syamal Roy
AFFILIATION: Department of Immunology, Indian Institute of Chemical Biology,
Kolkata, India.
REFERENCE: J Immunol 2005 Jun 174(11):7160-71
The emergence of an increasing number of Leishmania donovani strains
resistant to pentavalent antimonials (SbV), the first line of treatment
for visceral leishmaniasis worldwide, accounts for decreasing efficacy
of chemotherapeutic interventions. A kinetoplastid membrane protein-11 (
KMP-11)-encoding construct protected extremely susceptible golden
hamsters from both pentavalent antimony responsive (AG83) and antimony
resistant (GE1F8R) virulent L. donovani challenge. All the KMP-11 DNA
vaccinated hamsters continued to survive beyond 8 mo postinfection, with
the majority showing sterile protection. Vaccinated hamsters showed
reversal of T cell anergy with functional IL-2 generation along with
vigorous specific anti-KMP-11 CTL-like response. Cytokines known to
influence Th1- and Th2-like immune responses hinted toward a complex
immune modulation in the presence of a mixed Th1/Th2 response in
conferring protection against visceral leishmaniasis. KMP-11 DNA
vaccinated hamsters were protected by a surge in IFN-gamma, TNF-alpha,
and IL-12 levels along with extreme down-regulation of IL-10.
Surprisingly the prototype candidature of IL-4, known as a disease
exacerbating cytokine, was found to have a positive correlation to
protection. Contrary to some previous reports, inducible NO synthase was
actively synthesized by macrophages of the protected hamsters with
concomitant high levels of NO production. This is the first report of a
vaccine conferring protection to both antimony responsive and resistant
Leishmania strains reflecting several aspects of clinical visceral
leishmaniasis.
PMID: 15901246
TITLE: Aquaporins from pathogenic protozoan parasites: structure, function and
potential for chemotherapy.
AUTHORS: Eric Beitz
AFFILIATION: Department of Pharmaceutical Chemistry, University of Tübingen,
Morgenstelle 8, D-72076 Tübingen, Germany.
REFERENCE: Biol Cell 2005 Jun 97(6):373-83
Infectious diseases, caused by protozoa, such as malaria, sleeping
sickness, Chagas' disease or leishmaniasis, are a global threat. The
increase in the number of affected individuals and the rapid spread of
drug-resistant strains call for specific novel strategies to combat
human pathogenic parasites. In the search for novel drug targets,
transport proteins for nutrients and metabolites of the parasite-host
interface are getting into focus. The present review summarizes and
discusses the currently available results on protozoan aquaporins.
Various genes coding for aquaporin water and solute channels have been
identified in the protozoan genomes and they are probable elements of
the parasite's cell membrane. Phylogenetic analysis reveals that
individual aquaporin genes are of bacterial or plant origin. So far, six
protozoan aquaporins have been cloned and functionally characterized.
Typically, these are bifunctional channels and pass water at
intermediate to high rates as well as uncharged solutes. In the present
review, amino acid compositions of the individual pore entries are
compared and permeability properties are attributed to specific protein
features. Furthermore, possible physiological roles in osmotic
protection and metabolism are discussed. Finally, the potential of
protozoan aquaporins for use as a target or entry pathway for
chemotherapeutic compounds is reviewed.
PMID: 15886638
TITLE: A case of mucocutaneous leishmaniasis.
AUTHORS: Gina R Virgilio, Braden R Hale
AFFILIATION: Naval Special Warfare Center Division, Naval Medical Center San
Diego, 34800 Bob Wilson Drive, San Diego, CA 92134, USA.
virgiliog at navspecwarcen.navy.mil
REFERENCE: Otolaryngol Head Neck Surg 2005 May 132(5):800-1
PMID: 15890115
TITLE: Risk factors for kala-azar in Bangladesh.
AUTHORS: Caryn Bern, Allen W Hightower, Rajib Chowdhury, Mustakim Ali, Josef
Amann, Yukiko Wagatsuma, Rashidul Haque, Katie Kurkjian, Louise E Vaz, Moarrita
Begum, Tangin Akter, Catherine B Cetre-Sossah, Indu B Ahluwalia, Ellen Dotson,
W Evan Secor, Robert F Breiman, James H Maguire
AFFILIATION: Division of Parasitic Diseases, National Center for Infectious
Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30341,
USA. Cbern at cdc.gov
REFERENCE: Emerg Infect Dis 2005 May 11(5):655-62
Since 1990, South Asia has experienced a resurgence of kala-azar (
visceral leishmaniasis). To determine risk factors for kala-azar, we
performed cross-sectional surveys over a 3-year period in a Bangladeshi
community. By history, active case detection, and serologic screening,
155 of 2,356 residents had kala-azar with onset from 2000 to 2003. Risk
was highest for persons 3-45 years of age, and no significant difference
by sex was seen. In age-adjusted multivariable models, 3 factors were
identified: proximity to a previous kala-azar patient (odds ratio [OR]
25.4, 95% confidence interval [CI] 15-44 within household; OR 3.2 95% CI
1.7-6.1 within 50 m), bed net use in summer (OR 0.7, 95% CI 0.53-0.93
), and cattle per 1,000 m2 (OR 0.8, 95% CI 0.70-0.94]). No difference
was seen by income, education, or occupation; land ownership or other
assets; housing materials and condition; or keeping goats or chickens
inside bedrooms. Our data confirm strong clustering and suggest that
insecticide-treated nets could be effective in preventing kala-azar.
PMID: 15899186
TITLE: [Spontaneous rupture of the spleen in a patient with visceral
leishmaniasis.]
AUTHORS: Rosa Elvira Rovira, José Ramón DÃaz-Gómez, Xelo Lapuebla, MarÃa
Carmen Aguar
AFFILIATION: Servicio de Medicina Interna y NeumologÃa. Hospital General de
Castellón. España.
REFERENCE: Enferm Infecc Microbiol Clin 2005 May 23(5):327
PMID: 15866511
TITLE: Sand fly specificity of saliva-mediated protective immunity in Leishmania
amazonensis-BALB/c mouse model.
AUTHORS: Maria Thiakaki, Iva Rohousova, Vera Volfova, Petr Volf, Kwang-Poo
Chang, Ketty Soteriadou
AFFILIATION: Department of Microbiology, Laboratory of Molecular Parasitology,
Hellenic Pasteur Institute, 127 Bas. Sofias Ave., 11521 Athens, Greece.
REFERENCE: Microbes Infect 2005 Apr 7(4):760-6
Immune response of BALB/c mice to the salivary antigens of sand flies
was found to vary with different species used, i.e. Phlebotomus papatasi
, Phlebotomus sergenti and Lutzomyia longipalpis. Exposure of mice to
bites of these sand flies elicits production of antibodies, which are
largely specific to different saliva antigens previously identified as
unique to the respective fly species. When immunized intradermally (i.d
.) with salivary gland lysates (SGL) of L. longipalpis, BALB/c mice
developed partial protective immunity against challenges in the
contralateral ears with Leishmania amazonensis plus the gland lysates.
Preimmunization of these mice with the lysates from the other two
species was ineffective, further indicative of the specificity of saliva
-mediated immune response. The partial protective immunity observed is
significant, although it is not as dramatic as reported previously in a
different sand fly-mouse model. There is a correlation of this immunity
with a lower number of mononuclear and polymorphonuclear phagocytes at
the site of parasite inoculation. Vector species-specificity of this
immunity implies its elicitation by unique saliva antigen-an issue which
requires attention when designing saliva-based vaccines against
leishmaniasis.
PMID: 15898448
TITLE: [Diagnosis and differential diagnosis of visceral leishmaniasis in Hunan
province]
AUTHORS: Guo-ping Zhang, Fang-ping Chen, Li-juan Feng
AFFILIATION: zhangguoping1968 at sina.com.cn
REFERENCE: Zhong Nan Da Xue Xue Bao Yi Xue Ban 2005 Apr 30(2):245-6
PMID: 15849344
TITLE: Two cases of feline leishmaniosis in Switzerland.
AUTHORS: S Rüfenacht, H Sager, N Müller, V Schaerer, A Heier, M M Welle, P J
Roosje
AFFILIATION: Dermatology Unit, Department of Clinical Veterinary Medicine,
University of Berne, Switzerland.
REFERENCE: Vet Rec 2005 Apr 156(17):542-5
Two cats with Leishmania species infections were investigated. The first
had been imported from Spain with a non-healing, ulcerated nodule on a
hindleg. The presence of Leishmania species was detected by
histopathology and pcr on samples of skin. The lesion was unresponsive
to treatment with allopurinol for three months but the cat was treated
successfully by removing the lesion surgically. The second cat had lived
in both Spain and Switzerland, and had a history of recurrent skin
lesions on its head and neck. A diagnosis of pemphigus foliaceus was
made on the basis of histopathology, but Leishmania species serology (
elisa) and pcr of skin were positive, leading to a diagnosis of a
Leishmania species infection combined with pemphigus foliaceus.
PMID: 15710544
TITLE: Effects of hyperbaric oxygen on Leishmania amazonensis promastigotes and
amastigotes.
AUTHORS: Wagner Weber Arrais-Silva, Marcelle Carolina Collhone, Diana Copi
Ayres, Paula Cristina de Souza Souto, Selma Giorgio
AFFILIATION: Department of Parasitology, Biology Institute, Universidade
Estadual de Campinas, Caixa Postal 6109, Cep 13083-970, Campinas, São Paulo,
Brazil.
REFERENCE: Parasitol Int 2005 Mar 54(1):1-7
In the present study, we evaluated the effects of hyperbaric oxygen (HBO
) exposure in both Leishmania amazonensis life stages (promastigotes and
amastigotes) and on macrophage cultures infected with the parasite. HBO
treatment protocols, which can be tolerated by humans and animals,
induced irreversible metabolic damage and affected parasite morphology,
growth and ability to transform. The observation that the antioxidant N-
acetylcysteine (NAC) prevents some of these deleterious effects
indicated an involvement of oxidative stress during parasite HBO
exposure. In addition, HBO exposed L. amazonensis-infected macrophage
cultures showed reduction of the percentage of infected cells and of the
number of intracellular parasites per cell. Thus, the demonstration
that HBO, a therapy used in the management of different diseases, is
toxic for both L. amazonensis life stages and can alter macrophage
susceptibility to the infection encourages further studies of this
therapy in animal models of Leishmania infection.
PMID: 15740861
TITLE: Clinical and serological follow-up in dogs with visceral leishmaniosis
treated with allopurinol and sodium stibogluconate.
AUTHORS: Serdar Pasa, Seray Ozensoy Toz, Huseyin Voyvoda, Yusuf Ozbel
AFFILIATION: Department of Internal Medicine, Faculty of Veterinary, University
of Adnan Menderes, Aydin 09016, Turkey. pasaserdar at yahoo.co.uk
REFERENCE: Vet Parasitol 2005 Mar 128(3-4):243-9
Seven dogs with parasitologically proven clinical visceral leishmaniosis
(Leishmania infantum infection) were treated with a combination of
allopurinol and sodium stibogluconate. The dogs received first orally 15
mg/kg of allopurinol every 12 h until the clinical signs improved, in
the following 1 month period allopurinol at same dose and subcutaneously
30 mg/kg of sodium stibogluconate combination were given daily and at
the end of the combined treatment, allopurinol was continued alone at
the same dose till the end of 8 months. During the treatment period,
dogs were supported by additional proteins, vitamins, and minerals. A
long acting insecticide (collar or drop) was also used in order to
prevent further parasite transmission. Follow-up was maintained by
clinical, clinicopathological evaluation, and parasitological
examination of lymph node, serology using the indirect immunofluorescent
antibody test (IFAT). Before treatment commenced, the most important
clinical signs were exfoliative dermatitis, ulcerations, peripheral
lymhadenopathy, pale mucous membranes, weight loss, and ocular lesions.
Clinicopathological findings included commonly anaemia,
hyperproteinaemia, hyperglobulinaemia and hypoalbuminaemia. Before the
treatment, amastigotes were seen in six of the seven dogs by examination
of lymph node aspiration, and IFAT-titers were positive in all dogs. At
the end of 8 months treatment, remission of clinical signs, restoration
to normal of clinicopathological abnormalities were noticed. Lymph node
aspiration was performed on three out of the seven dogs at the end of
the treatment because of the very small sizes of the lymph nodes, and no
amastigotes were observed. Although the mean IFAT-titer of the dogs
were significantly (P < 0.001) lower compared with pretreatment, IFAT
-titers of dogs were still positive. No relapses occurred during
treatment period and a 6-24-month duration after the end of therapy.
Based on the above results, long-term use of allopurinol combined with
sodium stibogluconate together with support treatment concluded to have
enough therapeutic efficacies in the treatment of dogs with visceral
leishmaniosis. Observations of the cases for possible relapses were
still going on and insecticide application was carefully carrying on in
order preventing a possible re-infection.
PMID: 15907761
TITLE: Polyamine transport in parasites: A potential target for new
antiparasitic drug development.
AUTHORS: Rosa MarÃa Reguera, Babu L Tekwani, Rafael Balaña-Fouce
AFFILIATION: Department of Pharmacology and Toxicology (INTOXCAL), University of
Leon, Campus de Vegazana (s/n) 24071 Leon, Spain.
REFERENCE: Comp Biochem Physiol C Toxicol Pharmacol 2005 Feb 140(2):151-64
The metabolism of the naturally occurring polyamines-putrescine,
spermidine and spermine-is a highly integrated system involving
biosynthesis, uptake, degradation and interconversion. Metabolic
differences in polyamine metabolism have long been considered to be a
potential target to arrest proliferative processes ranging from cancer
to microbial and parasitic diseases. Despite the early success of
polyamine inhibitors such as alpha-difluoromethylornithine (DFMO) in
treating the latter stages of African sleeping sickness, in which the
central nervous system is affected, they proved to be ineffective in
checking other major diseases caused by parasitic protozoa, such as
Chagas' disease, leishmaniasis or malaria. In the use and design of new
polyamine-based inhibitors, account must be taken of the presence of up-
regulated polyamine transporters in the plasma membrane of the
infectious agent that are able to circumvent the effect of the drug by
providing the parasite with polyamines from the host. This review
contains information on the polyamine requirements and molecular,
biochemical and genetic characterization of different transport
mechanisms in the parasitic agents responsible for a number of the
deadly diseases that afflict underdeveloped and developing countries.
PMID: 15903079
TITLE: [Role of vitamin deficiency in pancytopenia in Djibouti. Findings in a
series of 81 consectutive patients]
AUTHORS: C Lavigne, E Lavigne, D Massenet, C Binet, J L Brémond, D Prigent
AFFILIATION: Service de médecine, Hôpital Général Peltier, Djiboutiville,
République de Djibouti. ChLavigne at chu-angers.fr
REFERENCE: Med Trop (Mars) 2005 65(1):59-63
The purpose of this study of patients with pancytopenia in Republic of
Djibouti was to identify etiologic factors and attempt to define
diagnostic and therapeutic strategies adapted to local conditions.
Clinical, biological and radiological assessment was performed in 81
patients hospitalized for pancytopenia. There were 56 men and 25 women.
Mean hemoglobin, leukocyte and platelet rates were 56,5 +/- 22,7 g/l, 2,
1 +/- 0,7.g/l and 56,2 +/- 24,7 g/l respectively. Vitamin deficiency was
the most common cause of pancytopenia (49%), followed by hypersplenism
(9%), HIV infection (6%) and leishmaniasis (6%). Vitamin-deficient
patients had significantly more severe anemia and thrombopenia and
significantly higher mean corpuscular volume than patients with
pancytopenia related to other causes. Hemoglobin rate lower than 40 g/L
and platelet rate lower than 35 G/L showed a positive predictive values
of 90% and 100% respectively for a vitamin deficient pancytopenia.
Vitamin deficiency is the most frequent etiology of pancytopenia and
causes the most severe cytopenia in Djibouti. Rapid vitamin
supplementation after minimal etiologic assessment including a myelogram
is an effective treatment strategy for this public health problem.
PMID: 15895173
TITLE: [American tegumentary leishmaniasis caused by Leishmania (Viannia)
braziliensis in military training area of Zona da Mata in Pernambuco]
AUTHORS: Maria S Andrade, Maria E F Brito, Salomão Thomaz da Silva, Bruna S
Lima, Ericka L Almeida, Elisângela L Albuquerque, José F Marinho Júnior,
Edna Ishikawa, Elisa Cupolillo, Sinval P Brandão-Filho
AFFILIATION: Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz,
Recife, PE, Brazil.
REFERENCE: Rev Soc Bras Med Trop 2005 May-Jun 38(3):229-33
The aim of work was to study the epidemiology of American tegumentary
leishmaniasis in a military training unit situated in Zona da Mata
region of Pernambuco State. Between 2002 and 2003 twenty-three cases
were notified by clinical exam, detection and/or isolation of parasite
and Montenegro skin test. Seven stocks of Leishmania (Viannia)
braziliensis were obtained from patients, identified by a panel of
specific monoclonal antibodies and isoenzymatic electrophoresis profiles
. An epidemiologic survey on prevalence of infection was carried out by
Montenegro skin test in the population that underwent training
activities during the same period, out of which 25.3% were identified as
positive. These results in association with previous data from this
area, shows the maintenance of a primary transmission cycle and the
occurrence of periodical outbreaks after training activities in local
areas of remnant Atlantic rain forest.
PMID: 15895170
TITLE: Retrospective study of 151 patients with cutaneous leishmaniasis treated
with meglumine antimoniate.
AUTHORS: Armando de Oliveira Schubach, Keyla B Feldman Marzochi, João Soares
Moreira, Tânia Maria Pacheco Schubach, Marcelo Lodi Araújo, Antônio Carlos
Francesconi do Vale, Sonia Regina Lambert Passos, Mauro Célio de Almeida
Marzochi
AFFILIATION: Centro de Referências em Leishmanioses, Instituto de Pesquisa
ClÃnica Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
armando at ipec.fiocruz.br
REFERENCE: Rev Soc Bras Med Trop 2005 May-Jun 38(3):213-7
We retrospectively analyzed a series of 151 cases of cutaneous
leishmaniasis treated between 1967 and 1982. One-hundred-and-thirty-nine
(92%) patients presented with active lesions and were treated with
daily doses of meglumine antimoniate: 81 adults received a 5-ml vial IM
and 58 children received 1 to 5 ml. Forty-five (32.4%) patients
underwent continuous treatment with meglumine antimoniate for 25 to 116
days without rest intervals, and 94 (67.6%) intermittent treatment with
2 to 5 series of meglumine antimoniate. Intermittent series could
include schedules of daily IM applications for 10 to 25 days each and
intervals varying from 10 to 60 days. Antimony dose was calculated for
66 (47.5%) patients and ranged from 3.9 to 28.7 Sb5+/kg/day. Of these,
35 patients received > or =10 mg and 31 patients < 10 mg Sb5+/kg/day
. Median time of healing was longer for lesions on the legs and feet --
67.5 days versus 48.7 days (p < 0.001) for other sites. However,
there were no significant differences in the median time of healing
between adults and children, intermittent and continuous regimens or
high and low antimony doses. Fifty-one patients were reassessed 5 to 14
years after treatment and showed no evidence of disease. These results
support further investigation (clinical trials) on treatment using low
doses of antimony.
PMID: 15895180
TITLE: [A fatal case of mucocutaneous leishmaniasis after pentavalent antimonial
use]
AUTHORS: Márcio Campos Oliveira, Rivadávio Fernandes Batista de Amorim,
Roseana de Almeida Freitas, Antonio de Lisboa Lopes Costa
AFFILIATION: Faculdade de Odontologia, Universidade Federal do Rio Grande do
Norte, Natal, RN.
REFERENCE: Rev Soc Bras Med Trop 2005 May-Jun 38(3):258-60
The authors report a case of mucocutaneous leishmaniasis in a 45-year-
old patient who was unsuccessfully treated with pentavalent antimonial
for 30 days. After 10 days from the initial treatment and before
starting a new therapeutic regimen with the same drug the patient died
due to sudden cardiac arrest.
PMID: 15846906
TITLE: [Immunization with Leishmania amazonensis subgenomic libraries protects
BALB/c mice against the challenge]
AUTHORS: Ana M MontalvoAlvarez, Lianet Monzote Fidalgo, Lisset Fonseca Géigel,
Ivón Montano Goodridge, Luis Fonte Galindo, Manuel Soto, José M Requena
AFFILIATION: Instituto de Medicina Tropical "Pedro Kouri" Ciudad de La Habana,
Cuba. amontalvo at ipk.sld.cu
REFERENCE: Rev Cubana Med Trop 2004 May-Aug 56(2):103-10
A genomic library of Leishmania amazonensis in expression vector of
eukaryote cells (pEF1HisA, pEF1HisB, pEF1HisC) was prepared. Also two
subgenomic libraries having each 500 clones approximately were created
and BALB/c mice were immunized with 50 mg/0,1 mL of DNA from each. Two
immunizations were administered intramuscularly at 15-day interval.
Groups of control mice were immunized with DNA from empty plasmid
pEF1His, with soluble parasite antigen (100 mg/0,1 mL) and saline
solution. The size of lesions was measured for 12 weeks and at the end
of the experiment, the parasite load at lesion sites was determined by
plaque microtitration method. In mice immunized with subgenomic library
DNAI and with soluble antigens,the size of lesions was controlled, which
reached an statistical difference (p< 0,05) in relation to the rest
of groups whose lesions increased. The parasite load found in lesion
sites confirmed the previous results; the number of promastigots was
significantly lower in those mice already protected. It was concluded
that in subgenomic library DNA1 there should be genes or gene fragments
whose in vivo expression induces protective immune response against the
challenge in the murine model used.
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The following references are revised files and are brought to you in accordance
to license agreement with the NLM.
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PMID: 11289063
TITLE: Kinetics of the intracellular differentiation of Leishmania amazonensis
and internalization of host MHC molecules by the intermediate parasite stages.
AUTHORS: N Courret, C Frehel, E Prina, T Lang, J C Antoine
AFFILIATION: Unité d' Immunophysiologie et Parasitisme Intracellulaire,
Institut Pasteur, Paris, France.
REFERENCE: Parasitology 2001 Mar 122(Pt 3):263-79
The establishment of Leishmania in mammals depends on the transformation
of metacyclic promastigotes into amastigotes within macrophages. The
kinetics of this process was examined using mouse macrophages infected
with metacyclic promastigotes of L. amazonensis. The appearance of
amastigote characteristics, including large lysosome-like organelles
called megasomes, stage-specific antigens, high cysteine protease
activity and sensitivity to L-leucine methyl ester, was followed over a
5-day period. Megasomes were observed at 48 h but probable precursors of
these organelles were detected at 12h p.i. The promastigote-specific
molecules examined were down-regulated within 5 to 12h after
phagocytosis whereas the amastigote-specific antigens studied were
detectable from 2 to 12-24 h. An increase in the cysteine protease
activity and in sensitivity to L-leucine methyl ester of the parasites
was detected from 24 h. The data indicate that at 48 h p.i., parasites
exhibit several amastigote features but that complete differentiation
requires at least 5 days. The appearance of megasomes or of megasome
precursors and the rise in cysteine protease activity correlate quite
well with the capacity of parasites to internalize and very likely
degrade host MHC molecules. The fact that internalization by the
parasites of host cell molecules occurs very early during the
differentiation process argues for a role of this mechanism in parasite
survival.
PMID: 9024203
TITLE: Leishmania major: comparison of the cathepsin L- and B-like cysteine
protease genes with those of other trypanosomatids.
AUTHORS: J A Sakanari, S A Nadler, V J Chan, J C Engel, C Leptak, J Bouvier
AFFILIATION: Department of Pathology, University of California, V. A. Medical
Center, San Francisco 94121, USA. jas at cgl.ucsf.edu
REFERENCE: Exp Parasitol 1997 Jan 85(1):63-76
Cysteine proteases play important roles in the pathogenesis of several
parasitic infections and have been proposed as targets for the structure
-based strategy of drug design. As a first step toward applying this
strategy to design inhibitors as antiparasitic agents for leishmaniasis
, we have isolated and sequenced the full-length clones of two cysteine
protease genes from Leishmania major. One of the genes is structurally
similar to the cathepsin L-like family and the other is similar to the
cathepsin B-like family of cysteine proteases. The L. major cathepsin L-
like sequence has a proregion that shares high sequence similarity with
other cathepsin L sequences but not cathepsin B sequences and has a
proline/threonine-rich C-terminal extension. The cathepsin L-like gene
occurs in multiple copies, whereas there may be only one copy of the
cathepsin B-like gene. Northern blot analyses show that both genes are
expressed in the promastigote and amastigote stages, and pulse field gel
electrophoresis revealed that the cathepsin L- and B-like genes are
each found on two nonhomologous chromosomes. The L. major L-like amino
acid sequence is 75% identical to the L. mexicana sequence, 74%
identical to the L. pifanoi sequence, 47% identical with the Trypanosoma
cruzi sequence, 47% identical with the T. congolense sequence, and 45%
identical with the T. brucei sequence. L. major is one of two
trypanosomatid species for which a cathepsin B-like gene has been
identified and sequenced; its amino acid sequence is 82% identical to
the one from L. mexicana. Tree inference based on distance and parsimony
methods of kinetoplastid cathepsin L proteins yielded independent
support for phylogenetic hypotheses inferred from analyses of ribosomal
RNA genes. Because the cathepsin L locus has a high level of
phylogenetic signal with respect to trypanosomatid taxa, this locus has
great potential utility for investigating the evolutionary history of
trypanosomatids and related organisms.
REQUEST: [ leishmania ]
(21 articles match this request. 9 articles matching other requests removed)
PMID: 15907560
TITLE: Identification of trypanosomatid PEX19: Functional characterization
reveals impact on cell growth and glycosome size and number.
AUTHORS: Sanjiban K Banerjee, Peter S Kessler, Tracy Saveria, Marilyn Parsons
AFFILIATION: Seattle Biomedical Research Institute, 307 Westlake Avenue N.,
Seattle, WA 98109, USA; Department of Pathobiology, School of Public Health and
Community Medicine, University of Washington, Seattle, WA 98195, USA.
REFERENCE: Mol Biochem Parasitol 2005 Jul 142(1):47-55
Glycosomes are peroxisome-like organelles present in trypanosomatid
pathogens. These organelles compartmentalize glycolysis, among other
reactions, and are essential in both bloodstream and procyclic form
Trypanosoma brucei. Peroxins (PEXs) are proteins necessary for
biogenesis of peroxisomes and glycosomes. In each assembled
trypanosomatid genome, we identified a predicted protein with
approximately 20% sequence identity to human PEX19, a protein required
for insertion of peroxisomal membrane proteins (PMPs) into the membrane
. Functional analysis demonstrated that these proteins are indeed PEX19
orthologues. Like other PEX19s, T. brucei and Leishmania major PEX19 GFP
fusion proteins are predominantly cytosolic. We further showed that
LmPEX19 interacts with the glycosomal membrane protein PEX2 in the yeast
two-hybrid system. Partial knockdown of TbPEX19 slowed parasite growth
, particularly when glucose was present. Immunofluorescence and electron
microscopic studies revealed biogenesis defect as evidenced by a sharp
reduction in the number of glycosomes. Surprisingly, a four-fold
increase in the size of the remaining glycosomes was observed. We
propose that this phenotype of fewer but larger glycosomes results from
the reduction in import of glycosomal membrane proteins.
PMID: 15907561
TITLE: Distinct overexpression of cytosolic and mitochondrial tryparedoxin
peroxidases results in preferential detoxification of different oxidants in
arsenite-resistant Leishmania amazonensis with and without DNA amplification.
AUTHORS: Yi-Chun Lin, Ju-Yu Hsu, Su-Chi Chiang, Sho Tone Lee
AFFILIATION: Division of Infectious Diseases, Institute of Biomedical Sciences,
Academia Sinica, Taipei 11529, Taiwan, ROC.
REFERENCE: Mol Biochem Parasitol 2005 Jul 142(1):66-75
A cytosolic (cTXNPx) and a mitochondrial (mTXNPx) tryparedoxin
peroxidase genes, cloned from wildtype Leishmania amazonensis clone 2-23
are homologous in nucleic acid and amino acid sequences to the
respective genes described for L. infantum and L. chagasi. Surprisingly
, as shown in the results of transcription assays, protein determination
and fluorescent antibody detection in situ, cTXNPx is distinctly
overexpressed in the cytoplasm of arsenite-resistant A variant with DNA
amplification, whereas mTXNPx is distinctly overexpressed in the
mitochondrion of arsenite-resistant A' variant without DNA amplification
, although A and A' are arsenite-resistant variants derived from the
same wildtype clone of L. amazonensis, and selected against arsenite
under the same conditions. Since the tunicamycin-resistant variant (T)
derived from the same W(2-23) clone and the hydroxyurea-resistant (Hu(2-
6)) variant derived from clone W(2-6) do not show overexpression of
these two genes, it is suggested that the distinct overexpression of
cTXNPx and mTXNPx genes in arsenite-resistant A and A' variants is
linked to arsenite selection process. These two genes in A and A'
variants, and cTXNPx(+) and mTXNPx(+) transfectants are similar to the
respective genes described for L. infantum and L. chagasi in terms of
antioxidant activities against H(2)O(2) and t-butyl hydroperoxide, in
which cTXNPx is more resistant to H(2)O(2), and mTXNPx is more resistant
to t-butyl hydroperoxide than the wildtype. Both genes, however, are
cross-resistant to NO as compared to the control wildtype. In the
transfectants carrying cTXNPx and mTXNPx in inverted orientation, these
two genes are expressed in a level lower than that in wildtype. The
decreased expression was followed by increased sensitivity of these
transfectants to the oxidants. This possibly is due to the formation of
antisense mRNA in these transfectants that causes a specific
downregulation of the respective genes.
PMID: 15878208
TITLE: An essential, putative MEK kinase of Leishmania major.
AUTHORS: Peter G Agron, Sharon L Reed, Joanne N Engel
AFFILIATION: Biology and Biotechnology Research Program, Lawrence Livermore
National Laboratory, Livermore, CA 94551, USA.
REFERENCE: Mol Biochem Parasitol 2005 Jul 142(1):121-5
PMID: 15876463
TITLE: Regulation of genes encoding the major surface protease of Leishmania
chagasi via mRNA stability.
AUTHORS: Jay E Purdy, John E Donelson, Mary E Wilson
AFFILIATION: Department of Internal Medicine, University of Iowa, Iowa City, IA
52242, USA.
REFERENCE: Mol Biochem Parasitol 2005 Jul 142(1):88-97
The intercoding regions between many Leishmania sp. genes regulate their
mRNA expression. The MSPL mRNA, encoding a subclass of the major
surface protease (MSP) of Leishmania chagasi, increases in abundance,
when protein synthesis is arrested, while alpha-tubulin (alpha-TUB) mRNA
and most other mRNAs do not. We found that the intercoding region
between MSPL-coding regions, when cloned downstream of the beta-
galactosidase reporter gene (beta-GAL), caused beta-GAL mRNA to increase
8- to 10-fold after inhibiting protein synthesis with cycloheximide.
Stable L. chagasi transfectants containing hybrid MSPL/alpha-TUB
intercoding regions cloned downstream of beta-GAL were made. The alpha-
TUB intercoding region induced high-level baseline beta-GAL mRNA that
increased only 1.3-fold after incubation with cycloheximide. In contrast
, the MSPL intercoding region, as well as constructs containing
nucleotides 303-505 from the MSPL 3'UTR, caused steady-state beta-GAL
mRNA levels in the absence of cycloheximide that were approximately 10%
of alpha-TUB constructs. These levels increased between 4.4- and 13.2-
fold after cycloheximide was added. Constructs containing half of this
region (303-394 or 395-505) produced intermediate levels of beta-GAL
mRNA and intermediate levels of cycloheximide induction. The kinetics of
cycloheximide induction of beta-GAL mRNA was similar with region 303-
505 constructs as with constructs bearing the entire endogenous MSPL
intercoding region. Furthermore, region 303-505 increased reporter mRNA
abundance after cycloheximide by increasing mRNA half-life. Hence, we
have identified a 202-nucleotide region within the MSPL 3'UTR that is in
part responsible for cycloheximide induction. We hypothesize that this
region may interact with labile regulatory protein factor(s).
PMID: 15908413
TITLE: Recombinant Cysteine Proteinase from Leishmania (Leishmania) chagasi
Implicated in Human and Dog T-Cell Responses.
AUTHORS: Paulo Henrique da Costa Pinheiro, Suzana de Souza Dias, Kelsen Dantas
Eulálio, Ivete L Mendonça, Simone Katz, Clara Lúcia Barbiéri
AFFILIATION: Division of Parasitology, Universidade Federal de São Paulo,
Escola Paulista de Medicina, Rua Botucatu, 862-6o andar, São Paulo, SP, Brazil
04023-062. barbiericl at ecb.epm.br.
REFERENCE: Infect Immun 2005 Jun 73(6):3787-9
High in vitro lymphoproliferative responses were induced in humans and
dogs by a recombinant Leishmania (Leishmania) chagasi cysteine
proteinase, with secretion of IFN-gamma in asymptomatic subjects or of
IFN-gamma, interleukin 4 (IL-4), and IL-10 in oligosymptomatic subjects
. In contrast, responses of symptomatic patients and dogs were lower,
with production of IL-4 and IL-10.
PMID: 15852008
TITLE: Transforming growth factor-beta controls T helper type 1 cell development
through regulation of natural killer cell interferon-gamma.
AUTHORS: Yasmina Laouar, Fayyaz S Sutterwala, Leonid Gorelik, Richard A Flavell
AFFILIATION: Section of Immunobiology, Yale University School of Medicine, New
Haven, Connecticut 06520, USA.
REFERENCE: Nat Immunol 2005 Jun 6(6):600-7
Interferon-gamma and interleukin 12 produced by the innate arm of the
immune system are important regulators of T helper type 1 (T(H)1) cell
development, but signals that negatively regulate their expression
remain controversial. Here we show that transforming growth factor-beta
(TGF-beta) controlled T(H)1 differentiation through the regulation of
interferon-gamma produced by natural killer (NK) cells. Blockade of TGF-
beta signaling in NK cells caused the accumulation of a large pool of NK
cells secreting copious interferon-gamma, responsible for T(H)1
differentiation and protection from leishmania infection. In contrast,
blockade of TGF-beta signaling in dendritic cells did not affect
dendritic cell homeostasis or interleukin 12 production, thus indicating
a previously undescribed demarcation of the function of TGF-beta in NK
cells versus dendritic cells.
PMID: 15752716
TITLE: Role of sulfhydryl groups in band 3 in the inhibition of phosphate
transport across erythrocyte membrane in visceral leishmaniasis.
AUTHORS: Sudipa Saha Roy, Gargi Sen, Tuli Biswas
AFFILIATION: Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road,
Kolkata 700 032, India.
REFERENCE: Arch Biochem Biophys 2005 Apr 436(1):121-7
Membrane destabilization in erythrocytes plays an important role in the
premature hemolysis and development of anemia during visceral
leishmaniasis (VL). Marked degradation of the anion channel protein band
3 is likely to allow modulation of anion flux across the red cell
membrane in infected animals. The present study describes the effect of
structural modification of band 3 on phosphate transport in VL using (31
)P NMR. The result showed progressive decrease in the rate and extent of
phosphate transport during the post-infection period. Interdependence
between the intracellular ionic levels seems to be a determining factor
in the regulation of anion transport across the erythrocyte membrane in
control and infected conditions. Infection-induced alteration in band 3
made the active sites of transport more susceptible to binding with
amino reactive agents. Inhibition of transport by oxidation of band 3
and subsequent reversal by reduction using dithiothreitol suggests the
contribution of sulfhydryl group in the regulation of anion exchange
across the membrane. Quantitation of sulfhydryl groups in the anion
channel protein showed the inhibition to be closely related to the
decrease of sulfhydryl groups in the infected hamsters. Downregulation
of phosphate transport during leishmanial infection may be ascribed to
the sulfhydryl modification of band 3 resulting in the impaired
functioning of this protein under the diseased condition.
PMID: 15895679
TITLE: Amidine derivatives and Leishmania amazonensis: an evaluation of the
effect of nitric oxide (NO) production on the parasite-macrophage interaction.
AUTHORS: R M Temporal, L Cysne-Finkelstein, A Echevarria, A J Silva-Gonçalves,
L L Leon, M S Genestra
AFFILIATION: Department of Immunology, Instituto Oswaldo Cruz/FIOCRUZ, Rio de
Janeiro, Brazil. temporal at ioc.fiocruz.br
REFERENCE: J Enzyme Inhib Med Chem 2005 Feb 20(1):13-8
Previous work has demonstrated that N-N'-diphenyl-R-benzamidine was
highly effective against Leishmania amazonensis promastigotes/axenic
amastigotes and Trypanosoma evansi trypomastigotes and the compound with
a methoxy substituent, was the most effective derivative in the
parasite-macrophage interaction. Comparative analysis of the nitric
oxide (NO) released from the culture infection's supernatant showed the
amidine to be less effective than pentamidine Isethionate as a reference
drug. Additionally, in order to verify if the methoxylated derivative
interferes with NO production by L. amazonensis, the effect of the
amidine on the constitutive nitric oxide synthase (cNOS) purified from
parasites, was examined, but demonstrated less activity in comparison
with the reference drug. This data contributes to studies concerning the
metabolic targets present in Leishmania parasites for leishmanicidal
drugs.
PMID: 15901047
TITLE: In vitro activities of thiadiazine derivatives against Leishmania
amazonensis.
AUTHORS: Lianet Monzote, Ana M Montalvo, Lisset Fonseca, Rolando Pérez,
Margarita Suárez, Hortensia RodrÃguez
AFFILIATION: Departamento de Parasitologia, Instituto de Medicina Tropical
"Pedro KourÃ", Ciudad de la Habana (Cuba). monzote at ipk.sld.cu
REFERENCE: Arzneimittelforschung 2005 55(4):232-8
Ten thiadiazine derivatives were tested in vitro for antiparasitic
effects against both extracellular promastigotes and intracellular
amastigotes of Leishmania amazonensis. The results showed that the
evaluated compounds exhibited a strong antiproliferative activity on all
developmental stages of the parasite. The minimal inhibitory
concentration and the 50 % effective concentration values against the
promastigote were 2.1-5.1 microg/ml and 0.6-1.8 microg/ml, respectively
. The tested compounds caused an irreversible inhibition of the
promastigote growth either after 1 h of treatment with 10 microg/ml or
after 24 h with 1 microg/ml. Also, the thiadiazine derivatives were
active against amastigotes producing between 12 and 89 % of reduction of
infection at 100 ng/ml. However, the compounds exhibited high toxicity
and provoked inhibition of the phagocytosis in the murine host cell.
********************************************************************************************************************
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PMID: 11231271
TITLE: S1 subsite specificity of a recombinant cysteine proteinase, CPB, of
Leishmania mexicana compared with cruzain, human cathepsin L and papain using
substrates containing non-natural basic amino acids.
AUTHORS: L C Alves, R L Melo, S J Sanderson, J C Mottram, G H Coombs, G
Caliendo, V Santagada, L Juliano, M A Juliano
AFFILIATION: Department of Biophysics, Escola Paulista de Medicina, Universidade
Federal de São Paulo, Brazil.
REFERENCE: Eur J Biochem 2001 Mar 268(5):1206-12
We have explored the substrate specificity of a recombinant cysteine
proteinase of Leishmania mexicana (CPB2.8 Delta CTE) in order to obtain
data that will enable us to design specific inhibitors of the enzyme.
Previously we have shown that the enzyme has high activity towards
substrates with a basic group at the P1 position [Hilaire, P.M.S., Alves
, L.C., Sanderson, S.J., Mottram, J.C., Juliano, M.A., Juliano, L.,
Coombs, G.H. & Meldal M. (2000) Chem. Biochem. 1, 115--122], but we
have also observed high affinity for peptides with hydrophobic residues
at this position. In order to have substrates containing both features,
we synthesized one series of internally quenched fluorogenic peptides
derived from the sequence ortho-amino-benzoyl-FRSRQ-N-[2,4-dinitrophenyl
]-ethylenediamine, and substituted the Arg at the P1 position with the
following non-natural basic amino acids: 4-aminomethyl-phenylalanine (
Amf), 4-guanidine-phenylalanine (Gnf), 4-aminomethyl-N-isopropyl-
phenylalanine (Iaf), 3-pyridyl-alanine (Pya), 4-piperidinyl-alanine (Ppa
), 4-aminomethyl-cyclohexyl-alanine (Ama), and 4-aminocyclohexyl-alanine
(Aca). For comparison, the series derived from ortho-amino-benzoyl-
FRSRQ-N-[2,4-dinitrophenyl]-ethylenediamine was also assayed with
cruzain (the major cysteine proteinase of Trypanosoma cruzi), human
cathepsin L and papain. The peptides ortho-amino-benzoyl-FAmfSRQ-N-[2,4-
dinitrophenyl]-ethylenediamine (k(cat)/K(m) = 12,000 mM(-1) x s(-1)) and
ortho-amino-benzoyl-FIafSRQ-N-[2,4-dinitrophenyl]-ethylenediamine (k(
cat)/K(m) = 27,000 mM(-1) x s(-1)) were the best substrates for CPB2.8
Delta CTE. In contrast, ortho-amino-benzoyl-FAmaSRQ-N-[2,4-dinitrophenyl
]-ethylenediamine and ortho-amino-benzoyl-FAcaSRQ-N-[2,4-dinitrophenyl]-
ethylenediamine were very resistant and inhibited this enzyme with K(i)
values of 23 nM and 30 nM, respectively. Cruzain hydrolyzed quite well
the substrates in this series with Amf, Ppa and Aca, whereas the peptide
with Ama was resistant and inhibited cruzain with a K(i) of 40 nM.
Human cathepsin L presented an activity on these peptides very similar
to that of CPB2.8 Delta CTE and papain hydrolyzed all the peptides with
high efficiency. In conclusion, we have demonstrated that CPB2.8 Delta
CTE has more restricted specificity at the S1 subsite and it seems
possible to design efficient inhibitors with amino acids such as Ama or
Aca at the P(1) position.
PMID: 9371086
TITLE: Leishmania major: molecular modeling of cysteine proteases and prediction
of new nonpeptide inhibitors.
AUTHORS: P M Selzer, X Chen, V J Chan, M Cheng, G L Kenyon, I D Kuntz, J A
Sakanari, F E Cohen, J H McKerrow
AFFILIATION: Department of Pathology, University of California, San Francisco
94143, USA. Paul.Selzer at med.uni-muenchen.de
REFERENCE: Exp Parasitol 1997 Nov 87(3):212-21
The crystal structures of papain, cruzain, and human liver cathepsin B
were used to build homology-based enzyme models of a cathepsin L-like
cysteine protease (cpL) and a cathepsin B-like cysteine protease (cpB)
from the protozoan parasite Leishmania major. Although structurally a
member of the cathepsin B subfamily, the L. major cpB is not able to
cleave synthetic substrates having an arginine in position P2. This
biochemical property correlates with the prediction of a glycine instead
of a glutamic acid at position 205 (papain numbering). The modeled
active sites of the L. major cpB and cpL were used to screen the
Available Chemicals Directory (a database of about 150,000 commercially
available compounds) for potential cysteine protease inhibitors, using
DOCK3.5. Based on both steric and force field considerations, 69
compounds were selected. Of these, 18 showed IC50's between 50 and 100
microM and 3 had IC50's below 50 microM. A secondary library of
compounds, originally derived from a structural screen against the
homologous protease of Plasmodium falciparum (falcipain), and
subsequently expanded by combinatorial chemistry, was also screened.
Three inhibitors were identified which were not only effective against
the L. major protease but also inhibited parasite growth at 5-50 microM.
PMID: 8008019
TITLE: Null mutants for the lmcpa cysteine proteinase gene in Leishmania
mexicana.
AUTHORS: A E Souza, P A Bates, G H Coombs, J C Mottram
AFFILIATION: Wellcome Unit of Molecular Parasitology, Institute of Genetics,
University of Glasgow, UK.
REFERENCE: Mol Biochem Parasitol 1994 Feb 63(2):213-20
The parasitic protozoon Leishmania mexicana possesses an abundance of
developmentally regulated cathepsin L-like cysteine proteinases
expressed at highest levels in amastigotes. We recently characterised
lmcpa, a single-copy gene encoding one such proteinase, LmCPa, which
differs from other homologues by possessing a 3-amino-acid insertion at
the amino terminal of the predicted mature proteinase. To investigate
the role of LmCPa in L. mexicana, we used gene-targeting of
promastigotes with hygromycin- and phleomycin-resistance markers to
generate null mutants by disrupting sequentially both alleles of lmcpa.
The promastigote null mutants did not differ significantly from wild-
type L. mexicana in growth rate or morphology and could differentiate to
metacyclics and the amastigote-like form, both of which could infect
the J774G8 macrophage-like cell line. The null mutant amastigote-like
form obtained from the J774G8 cells could also establish rump lesions in
CBA mice. By these criteria, therefore, LmCPa appears to be non-
essential although there is the possibility that LmCPa could be required
during development in the sandfly, a stage not analysed here. The
apparent redundancy of LmCPa in amastigotes may be due to the presence
of other cysteine proteinases and has implications for the choice of
candidate targets for rationally designed anti-leishmanial drugs.
REQUEST: [ sand fly ]
(1 article matches this request. 1 article matching other requests removed)
REQUEST: [ sandfly ]
(2 articles match this request. 1 article matching other requests removed)
PMID: 15895182
TITLE: [Phlebotomine sandflies in fragments of rain forest in Recife, Pernambuco
State]
AUTHORS: DÃlvia Ferreira Silva, Simão Dias Vasconcelos
AFFILIATION: Laboratório de Leishmaniose e Doença de Chagas, Centro de
Pesquisa em Ciência da Saúde, Instituto Nacional de Pesquisas da Amazônia,
Manaus, AM. dilvia at inpa.gov.br
REFERENCE: Rev Soc Bras Med Trop 2005 May-Jun 38(3):264-6
An investigation was conducted into the distribution of sandfly fauna in
4 fragments of Atlantic forest in the Metropolitan Area of Recife. It
consisted of the capture adult insects using CDC light traps. A total of
1,173 specimens were distributed in 11 species of Lutzomyia: Lutzomyia
evandroi, Lutzomyia choti, Lutzomyia walkeri, Lutzomyia umbratilis,
Lutzomyia brasiliensis, Lutzomyia sordellii, Lutzomyia claustrei,
Lutzomyia wellcomei, Lutzomyia fluviatilis, Lutzomyia furcata e
Lutzomyia aragaoi.
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