Tuesday, June 30, 2009

What's new for 'Trypanosomatids' in PubMed

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Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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PubMed Results
Items 1 -8 of 8

1: Iran J Immunol. 2009 Jun;6(2):75-86.

Expression of Recombinant Heat-Shock Protein 70 of MCAN/IR/96/LON-49, a Tool for Diagnosis and Future Vaccine Research.

Rasouli M, Zavaran Hoseini A, Kazemi B, Alborzi A, Kiany S.

Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Email: zavarana@modares.ac.i.

Background: Heat shock protein 70 (HSP70) is present in all organisms studied so far, and is a major immunogen in infections caused by pathogens including Leishmania spp. Objective: The aim of this study was to clone and express HSP70 from L. infantum strain MCAN/IR/96/LON-49 and evaluate antibody response against HSP70 in visceral leishmaniasis (VL). Methods: The L. infantum HSP70 gene segment was amplified by specific primers. It was cloned into pTZ57R vector and subcloned into pET32a (+) expression vector. The new construct was transformed in the E.coli Rosetta strain, and HSP70 protein was expressed in the presence of 1 mM IPTG and purified using a HiTrap chelating column. Antibody responses against HSP70 were determined by ELISA in 37 patients with visceral leishmaniasis and 63 healthy controls. Results: Expression of HSP70 protein was confirmed using SDS-PAGE electrophoresis and dot blot with an anti-His tag antibody. There was no difference between the sequence of nucleotides of the HSP70 gene in the present study and other reported sequences. The ELISA results indicated that the sera of 81.1% (30/37) of the patients and 6.3% (5/63) of controls reacted to L. infantum HSP70. Conclusion: The conservative nature of the HSP70 molecule is an advantage in vaccine studies, because of minor differences (6%) between the nucleotide sequences and consequently the similarity in amino acid sequences in various strains of L. infantum. It could therefore be used in vaccine research against leishmaniasis and also as a tool for serodiagnosis.

PMID: 19561376 [PubMed - in process]

2: J Infect. 2009 Jun 6. [Epub ahead of print]Click here to read

Immune response to Leishmania antigen in anthroponotic cutaneous leishmaniasis.

Ajdary S, Riazi-Rad F, Alimohammadian MH, Pakzad SR.

Immunology department, Pasteur Institute of Iran, Pasteur Ave., Postal code 13164, Tehran, Islamic Republic of Iran.

BACKGROUND: Leishmania (L.) tropica is the causative agent of anthroponotic cutaneous leishmaniasis (ACL) in Iran. The disease often heals within a year; however, the non-healing forms of disease are also known. The immunologic responses to L. major infection have been studied in depth, however little is known about the immune status of L. tropica-infected patients. MATERIALS AND METHODS: This study was conducted to evaluate T-cell responses to Leishmania antigen in non-healing patients, patients with acute lesion, and healthy donors. Peripheral blood mononuclear cells (PBMC) were cultured with antigen and lymphoproliferative responses were determined. Cytokine profile including gamma interferon (IFN-gamma), interleukin (IL)-5, and IL-13 in supernatants of stimulated cells was also determined. RESULTS: The results showed PBMC from both groups of patients proliferated vigorously in response to Leishmania antigens. The levels of IFN-gamma and IL-13 were comparable between patients with acute lesions and non-healing patients. Non-healing patients had significantly higher median levels of IL-5 than patients with acute lesions. The cells from healthy individuals did not respond to Leishmania antigens. CONCLUSIONS: High levels of IFN-gamma, IL-5, and IL-13 in non-healing patients suggest a mixed Th1/Th2 response, whereas patients with acute lesion respond to infection by Th1-type response.

PMID: 19560211 [PubMed - as supplied by publisher]

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3: Mol Biochem Parasitol. 2009 Jun 24. [Epub ahead of print]Click here to read

Analysis of expressed sequence tags from the four main developmental stages of Trypanosoma congolense.

Helm JR, Hertz-Fowler C, Aslett M, Berriman M, Sanders M, Quail MA, Soares MB, Bonaldo MF, Sakurai T, Inoue N, Donelson JE.

Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242 USA.

Trypanosoma congolense is one of the most economically important pathogens of livestock in Africa. Culture-derived parasites of each of the three main insect stages of the T. congolense life cycle, i.e., the procyclic, epimastigote and metacyclic stages, and bloodstream stage parasites isolated from infected mice, were used to construct stage-specific cDNA libraries and expressed sequence tags (ESTs or cDNA clones) in each library were sequenced. Thirteen EST clusters encoding different variant surface glycoproteins (VSGs) were detected in the metacyclic library and twenty-six VSG EST clusters were found in the bloodstream library, six of which are shared by the metacyclic library. Rare VSG ESTs are present in the epimastigote library, and none were detected in the procyclic library. ESTs encoding enzymes that catalyze oxidative phosphorylation and amino acid metabolism are about twice as abundant in the procyclic and epimastigote stages as in the metacyclic and bloodstream stages. In contrast, ESTs encoding enzymes involved in glycolysis, the citric acid cycle and nucleotide metabolism are about the same in all four developmental stages. Cysteine proteases, kinases and phosphatases are the most abundant enzyme groups represented by the ESTs. All four libraries contain T. congolense-specific expressed sequences not present in the T. brucei and T. cruzi genomes. Normalized cDNA libraries were constructed from the metacyclic and bloodstream stages, and found to be further enriched for T. congolense-specific ESTs. Given that cultured T. congolense offers an experimental advantage over other African trypanosome species, these ESTs provide a basis for further investigation of the molecular properties of these four developmental stages, especially the epimastigote and metacyclic stages for which it is difficult to obtain large quantities of organisms. The T. congolense EST databases are available at: http://www.sanger.ac.uk/Projects/T_congolense/EST_index.shtml.

PMID: 19559733 [PubMed - as supplied by publisher]

4: Curr Opin Immunol. 2009 Jun 24. [Epub ahead of print]Click here to read

Human innate immunity against African trypanosomes.

Pays E, Vanhollebeke B.

Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles, 12, rue des Professeurs Jeener et Brachet, B-6041 Gosselies, Belgium.

Humans are naturally resistant to infection by the African trypanosome prototype Trypanosoma brucei brucei, and only two variant clones of this parasite can avoid this innate immunity and cause sleeping sickness. The resistance to T. brucei is due to serum complexes associating apolipoprotein A-1 (apoA1) with two primate-specific proteins, apolipoprotein L-1 (apoL1) and haptoglobin-related protein (Hpr). We discuss recent advances on the respective functions of apoL1 and Hpr in this system. ApoL1 was found to share structural and functional similarities with proteins of the apoptotic Bcl2 family, and to kill trypanosomes through anionic pore formation in the lysosomal membrane of the parasite. In association with hemoglobin (Hb), Hpr was found to promote the binding of the trypanolytic complexes to a haptoglobin (Hp)-Hb receptor of the trypanosome surface, hereby facilitating the internalization of apoL1. Hpr or apoL1 deficiency respectively leads to the reduction or abolishment of human protection against T. brucei.

PMID: 19559585 [PubMed - as supplied by publisher]

5: Vet Parasitol. 2009 Jun 6. [Epub ahead of print]Click here to read

Directions for the diagnosis, clinical staging, treatment and prevention of canine leishmaniosis.

Solano-Gallego L, Koutinas A, Miró G, Cardoso L, Pennisi MG, Ferrer L, Bourdeau P, Oliva G, Baneth G.

Dep. Pathology and Infectious Diseases, Royal Veterinary College, University of London, Hawkshead Lane, North Mymms, Hatfield, Herts AL9 7TA, UK.

Canine leishmaniosis (CanL) due to Leishmania infantum is a life threatening zoonotic disease with a wide distribution in four continents and importance also in non-endemic regions. The purpose of this report is to present a consensus of opinions on the diagnosis, treatment, prognosis and prevention of CanL in order to standardize the management of this infection. CanL is a disease in which infection does not equal clinical illness due to the high prevalence of subclinical infection among endemic canine populations. The most useful diagnostic approaches include serology by quantitative techniques and PCR. High antibody levels are associated with severe parasitism and disease and are diagnostic of clinical leishmaniosis. However, the presence of lower antibody levels is not necessarily indicative of disease and further work-up is necessary to confirm CanL by other diagnostic methods such as cytology, histopathology and PCR. We propose a system of four clinical stages, based on clinical signs, clinicopathological abnormalities and serological status. Suitable therapy and expected prognosis are presented for each of the stages. The combination of meglumine antimoniate and allopurinol constitutes the first line pharmaceutical protocol. However, although most dogs recover clinically after therapy, complete elimination of the parasite is usually not achieved and infected dogs may eventually relapse. Follow-up of treated dogs with blood counts, serum biochemistry, urinalysis, serology and PCR is essential for prevention of relapses. Protection against sand fly bites by topical insecticides is effective in reducing infection, and recent development of vaccines has indicated that prevention by vaccination is feasible.

PMID: 19559536 [PubMed - as supplied by publisher]

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  • Allopurinol (Aloprim® , Zyloprim® )

    Allopurinol is used to treat gout, high levels of uric acid in the body caused by certain cancer medications, and kidney stones. Allopurinol is in a class of medications called xanthine oxidase inhibitors. It works by re...

  • Source: AHFS Consumer Medication Information
6: Lancet. 2009 Jun 24. [Epub ahead of print]Click here to read

Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial.

Priotto G, Kasparian S, Mutombo W, Ngouama D, Ghorashian S, Arnold U, Ghabri S, Baudin E, Buard V, Kazadi-Kyanza S, Ilunga M, Mutangala W, Pohlig G, Schmid C, Karunakara U, Torreele E, Kande V.

Epicentre, Paris, France.

BACKGROUND: Human African trypanosomiasis (HAT; sleeping sickness) caused by Trypanosoma brucei gambiense is a fatal disease. Current treatment options for patients with second-stage disease are toxic, ineffective, or impractical. We assessed the efficacy and safety of nifurtimox-eflornithine combination therapy (NECT) for second-stage disease compared with the standard eflornithine regimen. METHODS: A multicentre, randomised, open-label, active control, phase III, non-inferiority trial was done at four HAT treatment centres in the Republic of the Congo and the Democratic Republic of the Congo. Patients aged 15 years or older with confirmed second-stage T b gambiense infection were randomly assigned by computer-generated randomisation sequence to receive intravenous eflornithine (400 mg/kg per day, every 6 h; n=144) for 14 days or intravenous eflornithine (400 mg/kg per day, every 12 h) for 7 days with oral nifurtimox (15 mg/kg per day, every 8 h) for 10 days (NECT; n=143). The primary endpoint was cure (defined as absence of trypanosomes in body fluids and a leucocyte count </=20 cells per muL) 18 months after treatment. Efficacy analyses were done in the intention-to-treat (ITT), modified ITT, and per-protocol (PP) populations. The non-inferiority margin for the difference in cure rates was defined as 10%. This study is registered with ClinicalTrials.gov, number NCT00146627. FINDINGS: One patient from the eflornithine group absconded after receiving the first dose, without any type of assessment done, and was excluded from all analyses. In the ITT population, 131 (91.6%) of 143 patients assigned to eflornithine and 138 (96.5%) of 143 patients assigned to NECT were cured at 18 months (difference -4.9%, one-sided 95% CI -0.3; p<0.0001). In the PP population, 122 (91.7%) of 133 patients in the eflornithine group and 129 (97.7%) of 132 in the NECT group were cured at 18 months (difference -6.0%, one-sided 95% CI -1.5; p<0.0001). Drug-related adverse events were frequent in both groups; 41 (28.7%) patients in the eflornithine group and 20 (14.0%) in the NECT group had major (grade 3 or 4) reactions, which resulted in temporary treatment interruption in nine and one patients, respectively. The most common major adverse events were fever (n=18), seizures (n=6), and infections (n=5) in the eflornithine group, and fever (n=7), seizures (n=6), and confusion (n=2) in the NECT group. There were four deaths, which were regarded as related to study drug (eflornithine, n=3; NECT, n=1). INTERPRETATION: The efficacy of NECT is non-inferior to that of eflornithine monotherapy. Since this combination treatment also presents safety advantages, is easier to administer (ie, infusion every 12 h for 7 days vs every 6 h for 14 days), and potentially protective against the emergence of resistant parasites, it is suitable for first-line use in HAT control programmes. FUNDING: Médecins Sans Frontières (Dutch section), Médecins Sans Frontières International, and the Drugs for Neglected Diseases Initiative.

PMID: 19559476 [PubMed - as supplied by publisher]

Patient Drug Information

  • Eflornithine (Vaniqa® )

    Eflornithine is used to slow the growth of unwanted hair on the face in women, usually around the lips or under the chin. Eflornithine works by blocking a natural substance that is needed for hair to grow and is located ...

  • Source: AHFS Consumer Medication Information
7: Vaccine. 2009 Jun 23. [Epub ahead of print]Click here to read

Immunogenicity of candidate chimeric DNA vaccine against tuberculosis and leishmaniasis.

Dey A, Kumar U, Sharma P, Singh S.

Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India.

Mycobacterium tuberculosis and Leishmania donovani are important intracellular pathogens, especially in Indian context. In India and other South East Asian countries, both these infections are highly endemic and in about 20% cases co-infection of these pathogens is reported. For both these pathogens cell mediated immunity plays most important role. The available treatment of these infections is either prolonged or cumbersome or it is ineffective in controlling the outbreaks and spread. Therefore, potentiation of a common host defense mechanism can be used to prevent both the infections simultaneously. In this study we have developed a novel chimeric DNA vaccine candidate comprising the esat-6 gene of M. tuberculosis and kinesin motor domain gene of L. donovani. After developing this novel chimera, its immunogenicity was studied in mouse model. The immune response was compared with individual constructs of esat-6 and kinesin motor domain. The results showed that immunization with chimeric DNA vaccine construct resulted in stronger IFN-gamma and IL-2 response against kinesin (3012+/-102 and 367.5+/-8.92pg/ml) and ESAT-6 (1334+/-46.5 and 245.1+/-7.72pg/ml) in comparison to the individual vaccine constructs. The reciprocal immune response (IFN-gamma and IL-2) against individual construct was lower (kinesin motor domain: 1788+/-36.48 and 341.8+/-9.801pg/ml and ESAT-6: 867.0+/-47.23 and 170.8+/-4.578pg/ml, respectively). The results also suggest that using the chimeric construct both proteins yielded a reciprocal adjuvant affect over each other as the IFN-gamma production against chimera vaccination is statistically significant (p<0.0001) than individual construct vaccination. From this pilot study we could envisage that the chimeric DNA vaccine construct may offer an attractive strategy in controlling co-infection of leishmaniasis and tuberculosis and have important implication in future vaccine design.

PMID: 19559111 [PubMed - as supplied by publisher]

8: Mol Microbiol. 2009 Jun 24. [Epub ahead of print]Click here to read

Dissecting the essentiality of the bifunctional trypanothione synthetase-amidase in Trypanosoma brucei using chemical and genetic methods.

Wyllie S, Oza SL, Patterson S, Spinks D, Thompson S, Fairlamb AH.

Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland, UK.

Summary The bifunctional trypanothione synthetase-amidase (TRYS) comprises two structurally distinct catalytic domains for synthesis and hydrolysis of trypanothione (N(1),N(8)-bis(glutathionyl)spermidine). This unique dithiol plays a pivotal role in thiol-redox homeostasis and in defence against chemical and oxidative stress in trypanosomatids. A tetracycline-dependent conditional double knockout of TRYS (cDKO) was generated in bloodstream Trypanosoma brucei. Culture of cDKO parasites without tetracycline induction resulted in loss of trypanothione and accumulation of glutathione, followed by growth inhibition and cell lysis after 6 days. In the absence of inducer, cDKO cells were unable to infect mice, confirming that this enzyme is essential for virulence in vivo as well as in vitro. To establish whether both enzymatic functions were essential, an amidase-dead mutant cDKO line was generated. In the presence of inducer, this line showed decreased growth in vitro and decreased virulence in vivo, indicating that the amidase function is not absolutely required for viability. The druggability of TRYS was assessed using a potent small molecule inhibitor developed in our laboratory. Growth inhibition correlated in rank order cDKO, single KO, wild-type and overexpressing lines and produced the predicted biochemical phenotype. The synthetase function of TRYS is thus unequivocally validated as a drug target by both chemical and genetic methods.

PMID: 19558432 [PubMed - as supplied by publisher]

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