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Sent on Tuesday, 2009 Feb 24Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
- 1: J Immunol. 2009 Mar 1;182(5):3084-94.
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Alternatively activated macrophages elicited by helminth infection can be reprogrammed to enable microbial killing.
Institute of Immunology and Infection Research, The University of Edinburgh, Edinburgh, United Kingdom.
The prime function of classically activated macrophages (activated by Th1-type signals, such as IFN-gamma) is microbial destruction. Alternatively activated macrophages (activated by Th2 cytokines, such as IL-4 and IL-13) play important roles in allergy and responses to helminth infection. We utilize a murine model of filarial infection, in which adult nematodes are surgically implanted into the peritoneal cavity of mice, as an in vivo source of alternatively activated macrophages. At 3 wk postinfection, the peritoneal exudate cell population is dominated by macrophages, termed nematode-elicited macrophages (NeMphi), that display IL-4-dependent features such as the expression of arginase 1, RELM-alpha (resistin-like molecule alpha), and Ym1. Since increasing evidence suggests that macrophages show functional adaptivity, the response of NeMphi to proinflammatory Th1-activating signals was investigated to determine whether a switch between alternative and classical activation could occur in macrophages differentiated in an in vivo infection setting. Despite the long-term exposure to Th2 cytokines and antiinflammatory signals in vivo, we found that NeMphi were not terminally differentiated but could develop a more classically activated phenotype in response to LPS and IFN-gamma. This was reflected by a switch in the enzymatic pathway for arginine metabolism from arginase to inducible NO synthase and the reduced expression of RELM-alpha and Ym1. Furthermore, this enabled NeMphi to become antimicrobial, as LPS/IFN-gamma-treated NeMphi produced NO that mediated killing of Leishmania mexicana. However, the adaptation to antimicrobial function did not extend to key regulatory pathways, such as IL-12 production, which remained unaltered.
PMID: 19234205 [PubMed - in process]
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- Role of IFN-gamma in regulating T2 immunity and the development of alternatively activated macrophages during allergic bronchopulmonary mycosis. [J Immunol. 2005]
- Acute cysticercosis favours rapid and more severe lesions caused by Leishmania major and Leishmania mexicana infection, a role for alternatively activated macrophages. [Cell Immunol. 2006]
- ReviewRole of T-cell derived cytokines in the downregulation of immune responses in parasitic and retroviral infection. [Immunol Rev. 1992]
- ReviewThe debate over the effector function of eosinophils in helminth infection: new evidence from studies on the regulation of vaccine immunity by IL-12. [Mem Inst Oswaldo Cruz. 1997]
- 2: J Immunol. 2009 Mar 1;182(5):3039-46.
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IL-17 Promotes Progression of Cutaneous Leishmaniasis in Susceptible Mice.
Department of Dermatology, Johannes Gutenberg-University, Mainz, Germany;
Resistance to leishmaniasis in C57BL/6 mice depends on Th1/Tc1 cells. BALB/c mice preferentially develop Th2 immunity and succumb to infection. We now assessed the role of IL-17 in cutaneous leishmaniasis. During the course of Leishmania major infection, BALB/c CD4 cells and neutrophils produced increased amounts of IL-17 as compared with cells from C57BL/6 mice. This increase was associated with significantly increased IL-23 release from L. major-infected BALB/c dendritic cells (DC), whereas IL-6 and TGF-beta1 production by BALB/c and C57BL/6 DC were comparable. Interestingly, lesion sizes in infected IL-17-deficient BALB/c mice were dramatically smaller and failed to progress as compared with those in control mice. Similar amounts of IL-4, IL-10, and IFN-gamma were produced by T cells from IL-17-deficient mice and control mice consistent with development of Th2-predominant immunity in all animals. Improved disease outcome was associated with decreased CXCL2-accumulation in lesion sites and decreased neutrophil immigration into lesions of infected IL-17-deficient mice confirming prior observations that enhanced neutrophil recruitment contributes to disease susceptibility in BALB/c mice. This study excludes an important facilitating role for IL-17 in Th1/Th2 development in L. major-infected BALB/c mice, and suggests that IL-23 production by L. major-infected DC maintains IL-17(+) cells that influence disease progression via regulation of neutrophil recruitment.
PMID: 19234200 [PubMed - in process]
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Related Articles
- Leishmania major-infected murine langerhans cell-like dendritic cells from susceptible mice release IL-12 after infection and vaccinate against experimental cutaneous Leishmaniasis. [Eur J Immunol. 2000]
- Interleukin 1alpha promotes Th1 differentiation and inhibits disease progression in Leishmania major-susceptible BALB/c mice. [J Exp Med. 2003]
- Dendritic cell-derived IL-12p40 homodimer contributes to susceptibility in cutaneous leishmaniasis in BALB/c mice. [J Immunol. 2007]
- ReviewAnti-leishmania effector functions of CD4+ Th1 cells and early events instructing Th2 cell development and susceptibility to Leishmania major in BALB/c mice. [Adv Exp Med Biol. 1998]
- ReviewThe role of the innate immune response in Th1 cell development following Leishmania major infection. [J Leukoc Biol. 1995]
- 3: Trans R Soc Trop Med Hyg. 2009 Feb 19. [Epub ahead of print]
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The methodological quality of cluster randomised controlled trials for managing tropical parasitic disease: a review of trials published from 1998 to 2007.
Department of Public Health & Epidemiology, School of Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
The aim of this review was to assess the methodological quality of cluster randomised controlled trials (CRCT) for the management of tropical parasitic disease published between 1998 and 2007. A literature survey was conducted using Medline for CRCTs of interventions aimed at managing any one of the six major tropical parasitic diseases: malaria, leishmaniasis, lymphatic filariasis, onchocerciasis, schistosomiasis and trypanosomiasis (Chagas disease). Information was extracted from the published articles in order that, for each trial, categorical responses could be made to a pre-specified list of 12 questions concerning issues relating to the methodological quality of the trial, including choice of design, generalisability, baseline assessment, blinding, use or non-use of a matched design, and accounting for the intraclass correlation in both design and analysis. The literature survey found 38 CRCTs. Of the 35 CRCTs that reported at least one human outcome, 27 were for interventions in the management of malaria whilst the rest were for managing leishmaniasis (4 trials), lymphatic filariasis (2 trials) and schistosomiasis (2 trials). For every one of the pre-specified questions that concerned an issue associated with methodological quality, the responses were consistent with the practice of trialists in relation to the given issue being generally poor.
PMID: 19232658 [PubMed - as supplied by publisher]
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- ReviewPhysiotherapy interventions for shoulder pain. [Cochrane Database Syst Rev. 2003]
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- ReviewChemotherapy for hormone-refractory prostate cancer. [Cochrane Database Syst Rev. 2006]
- ReviewInterventions for the treatment of burning mouth syndrome. [Cochrane Database Syst Rev. 2001]
- 4: Trans R Soc Trop Med Hyg. 2009 Feb 19. [Epub ahead of print]
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Prevalence of Leishmania infection in adult HIV/AIDS patients treated in a tertiary-level care center in Brasilia, Federal District, Brazil.
Laboratório de Leishmanioses do Núcleo de Medicina Tropical, Universidade de Brasília, Campus Universitário, Asa Norte, Caixa Postal 04517, Brasília, DF 70904-970, Brazil; Hospital Universitário de Brasília, Av. L2 Norte S/N, Brasília, DF 70900-970, Brazil.
In order to estimate the magnitude of Leishmania/HIV co-infection, patients with HIV/AIDS at the Brasilia University Hospital, DF, Brazil were used as subjects in a cross-sectional study. One hundred and sixty-three patients were enrolled, seven of whom had visceral leishmaniasis (VL). One hundred and twelve patients (68.7%) were men; 155 (95.1%) had been exposed to HIV infection through unprotected sex. The median age was 37 years (range: 20-74) and the median CD4+ lymphocyte count was 314cells/mul (range: 2-1600). Symptomatic patients underwent bone marrow evaluations through direct examination of Giemsa-stained films, parasite culture and PCR assay. Blood samples were evaluated by means of an indirect immunofluorescent antibody test (IFAT), an ELISA using a soluble antigen of L. chagasi (ELISA), an ELISA with the rK39 antigen (ELISA-rK39) and a PCR targeted to the kDNA region and to the internal transcribed spacer 1 of the rDNA gene. The proportion of positive results was 2.4% for the IFAT, 12.3% for the ELISA and 4.9% for the rK39 tests. The estimated prevalence was 16%. The PCR in the blood was positive in three patients (1.8%). The prevalence of Leishmania spp. infection is high among HIV patients attending this Brazilian center suggesting that they should be routinely investigated for VL infection.
PMID: 19232657 [PubMed - as supplied by publisher]
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- Comparative evaluation of direct agglutination test, rK39 and soluble antigen ELISA and IFAT for the diagnosis of visceral leishmaniasis. [Trans R Soc Trop Med Hyg. 2008]
- The high sensitivity of a PCR-ELISA in the diagnosis of cutaneous and visceral leishmaniasis caused by Leishmania infantum. [Ann Trop Med Parasitol. 2002]
- Visceral leishmaniasis in HIV-1-infected individuals: a common opportunistic infection in Spain? [AIDS. 1992]
- ReviewClinical use of polymerase chain reaction performed on peripheral blood and bone marrow samples for the diagnosis and monitoring of visceral leishmaniasis in HIV-infected and HIV-uninfected patients: a single-center, 8-year experience in Italy and review of the literature. [Clin Infect Dis. 2007]
- ReviewLeishmania/HIV co-infection in Brazil: an appraisal. [Ann Trop Med Parasitol. 2003]
- 5: Bioorg Med Chem. 2009 Feb 4. [Epub ahead of print]
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Inhibition of Trypanosoma brucei glucose-6-phosphate dehydrogenase by human steroids and their effects on the viability of cultured parasites.
Centro de Biologia Molecular Estrutural, Instituto de Física de São Carlos, Universidade de São Paulo, Av. Trabalhador São Carlense 400, São Carlos, Brazil.
Dehydroepiandrosterone (DHEA) is known as an intermediate in the synthesis of mammalian steroids and a potent uncompetitive inhibitor of mammalian glucose-6-phosphate dehydrogenase (G6PDH), but not the enzyme from plants and lower eukaryotes. G6PDH catalyzes the first step of the pentose-phosphate pathway supplying cells with ribose 5-phosphate, a precursor of nucleic acid synthesis, and NADPH for biosynthetic processes and protection against oxidative stress. In this paper we demonstrate that also G6PDH of the protozoan parasite Trypanosoma brucei is uncompetitively inhibited by DHEA and epiandrosterone (EA), with K(i) values in the lower micromolar range. A viability assay confirmed the toxic effect of both steroids on cultured T. brucei bloodstream form cells. Additionally, RNAi mediated reduction of the G6PDH level in T. brucei bloodstream forms validated this enzyme as a drug target against Human African Trypanosomiasis. Together these findings show that inhibition of G6PDH by DHEA derivatives may lead to the development of a new class of anti-trypanosomatid compounds.
PMID: 19231202 [PubMed - as supplied by publisher]
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- The enzymes of the classical pentose phosphate pathway display differential activities in procyclic and bloodstream forms of Trypanosoma brucei. [FEBS Lett. 1989]
- Structure-based design of submicromolar, biologically active inhibitors of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase. [Proc Natl Acad Sci U S A. 1999]
- ReviewDehydroepiandrosterone, glucose-6-phosphate dehydrogenase, and longevity. [Ageing Res Rev. 2004]
- ReviewInhibition of tumor development by dehydroepiandrosterone and related steroids. [Toxicol Pathol. 1986]
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