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Transgenic leishmania

Sanjay Varikuti, Gayathri Natarajan, Steve Oghumu, Rachel H Sperling, Ellen Moretti, James Stock, Tracey L Papenfuss, Abhay R Satoskar
The outcome of visceral leishmaniasis, caused by parasite Leishmania donovani, depends on the recruitment of leishmanicidal Th1 cells. Chemokine receptor CXCR3, preferentially expressed by Th1 cells, is critical for migration of these T cells during infection. During chronic VL, there is a decrease in the presence of CXCR3-expressing CD4(+) T cells in the spleen, which is associated with high parasitic burden in this organ. We therefore examined whether T cell-specific expression of CXCR3 in mice (CXCR3(Tg)) would promote resistance to VL...
September 6, 2016: Cellular Immunology
Penta Ashok, Subhash Chander, Ana Tejería, Laura García-Calvo, Rafael Balaña-Fouce, Sankaranarayanan Murugesan
In the present study, antileishmanial activity of sixteen novel series of tetrahydro-β-carboline derivatives against transgenic infrared fluorescent Leishmania infantum strain has been reported. Among these reported analogues, most of the compounds exhibited potent inhibition against both promastigote (IC50 from 1.99 ± 1.40 to 20.69 ± 0.95 μM) and amastigote (IC50 from 0.67 ± 0.05 to 4.16 ± 0.008 μM) forms of L. infantum. Moreover, compound 7l, displayed most potent and selective inhibition of parasite amastigote form with IC50 0...
November 10, 2016: European Journal of Medicinal Chemistry
Kwang Poo Chang, Bala K Kolli
Light is known to excite photosensitizers (PS) to produce cytotoxic reactive oxygen species (ROS) in the presence of oxygen. This modality is attractive for designing control measures against animal diseases and pests. Many PS have a proven safety record. Also, the ROS cytotoxicity selects no resistant mutants, unlike other drugs and pesticides. Photodynamic therapy (PDT) refers to the use of PS as light activable tumoricides, microbicides and pesticides in medicine and agriculture.Here we describe "photodynamic vaccination" (PDV) that uses PDT-inactivation of parasites, i...
2016: Parasites & Vectors
Ruchir Rastogi, Jitender Kumar Verma, Anjali Kapoor, Gordon Langsley, Amitabha Mukhopadhyay
Differential functions of Rab5 isoforms in endocytosis are not well characterized. Here, we cloned, expressed, and characterized Rab5a and Rab5b from Leishmania and found that both of them are localized in the early endosome. To understand the role of LdRab5 isoforms in different modes of endocytosis in Leishmania, we generated transgenic parasites overexpressing LdRab5a, LdRab5b, or their dominant-positive (LdRab5a:Q93L and LdRab5b:Q80L) or dominant-negative mutants (LdRab5a:N146I and LdRab5b:N133I). Using LdRab5a or its mutants overexpressing parasites, we found that LdRab5a specifically regulates the fluid-phase endocytosis of horseradish peroxidase and also specifically induced the transport of dextran-Texas Red to the lysosomes...
July 8, 2016: Journal of Biological Chemistry
Estefanía Calvo-Álvarez, Raquel Álvarez-Velilla, Maribel Jiménez, Ricardo Molina, Yolanda Pérez-Pertejo, Rafael Balaña-Fouce, Rosa M Reguera
[This corrects the article DOI: 10.1371/journal.pntd.0003075.].
May 2016: PLoS Neglected Tropical Diseases
Tatiana Pineda, Yesenia Valencia, María F Flórez, Sergio A Pulido, Iván D Vélez, Sara M Robledo
Leishmaniasis is a parasitic infection caused by several species of the genus Leishmania that is considered as a neglected disease. Drug development process requires a robust and updated high-throughput technology to the evaluation of candidate compounds that imply the manipulation of the pathogenic species of the parasite in the laboratory. Therefore, it is restricted to trained personal and level II biosafety environments. However, it has been established the utility of Leishmania tarentolae as a model for in vitro screening of antileishmanial agents without the necessity of level II biosafety setups...
August 2016: Parasitology
Adriano C Coelho, Jordana C Oliveira, Caroline R Espada, Juliana Q Reimão, Cristiana T Trinconi, Silvia R B Uliana
BACKGROUND: Leishmania braziliensis is the most prevalent species isolated from patients displaying cutaneous and muco-cutaneous leishmaniasis in South America. However, there are difficulties for studying L. braziliensis pathogenesis or response to chemotherapy in vivo due to the natural resistance of most mouse strains to infection with these parasites. The aim of this work was to develop an experimental set up that could be used to assess drug efficacy against L. braziliensis. The model was tested using miltefosine...
May 2016: PLoS Neglected Tropical Diseases
Samuel M Duncan, Elmarie Myburgh, Cintia Philipon, Elaine Brown, Markus Meissner, James Brewer, Jeremy C Mottram
Leishmania mexicana has a large family of cyclin-dependent kinases (CDKs) that reflect the complex interplay between cell cycle and life cycle progression. Evidence from previous studies indicated that Cdc2-related kinase 3 (CRK3) in complex with the cyclin CYC6 is a functional homologue of the major cell cycle regulator CDK1, yet definitive genetic evidence for an essential role in parasite proliferation is lacking. To address this, we have implemented an inducible gene deletion system based on a dimerised Cre recombinase (diCre) to target CRK3 and elucidate its role in the cell cycle of L...
June 2016: Molecular Microbiology
Radika Soysa, Khoa D Tran, Buddy Ullman, Phillip A Yates
We have designed a novel series of integrating ribosomal RNA promoter vectors with five incrementally different constitutive expression profiles, covering a 250-fold range. Differential expression was achieved by placing different combinations of synthetic or leishmanial DNA sequences upstream and downstream of the transgene coding sequence in order to modulate pre-mRNA processing efficiency and mRNA stability, respectively. All of the vectors have extensive multiple cloning sites, and versions are available for producing N- or C- terminal GFP fusions at each of the possible relative expression levels...
December 2015: Molecular and Biochemical Parasitology
Michael J Dagley, Eleanor C Saunders, Kaylene J Simpson, Malcolm J McConville
Leishmania species are sandfly-transmitted protozoan parasites that cause a spectrum of diseases, ranging from localized skin lesions to fatal visceral disease, in more than 12 million people worldwide. These parasites primarily target macrophages in their mammalian hosts and proliferate as non-motile amastigotes in the phagolysosomal compartment of these cells. High-throughput screens for measuring Leishmania growth within this intracellular niche are needed to identify host and parasite factors that are required for virulence and to identify new drug candidates...
September 2015: Assay and Drug Development Technologies
Cesar Terrazas, Steve Oghumu, Sanjay Varikuti, Diana Martinez-Saucedo, Stephen M Beverley, Abhay R Satoskar
Host-pathogen interaction is an area of considerable interest. Intracellular parasites such as Leishmania reside inside phagocytes such as macrophages, dendritic cells and neutrophils. Macrophages can be activated by cytokines such as IFN-γ and Toll like receptor (TLR) agonists resulting in enhanced microbicidal activity. Leishmania parasites hijack the microbicidal function of macrophages, mainly by interfering with intracellular signaling initiated by IFN-γ and TLR ligands. Here we used transgenic Leishmania donovani parasites expressing the red fluorescent protein DsRed2 and imaging-flow cytometry technology to evaluate parasitic loads inside the macrophage in vitro...
August 2015: Journal of Immunological Methods
Amalia Papadaki, Anastasia S Politou, Despina Smirlis, Maria P Kotini, Konstadina Kourou, Thomais Papamarcaki, Haralabia Boleti
Acid ecto-phosphatase activity has been implicated in Leishmania donovani promastigote virulence. In the present study, we report data contributing to the molecular/structural and functional characterization of the L. donovani LdMAcP (L. donovani membrane acid phosphatase), member of the histidine acid phosphatase (HAcP) family. LdMAcP is membrane-anchored and shares high sequence identity with the major secreted L. donovani acid phosphatases (LdSAcPs). Sequence comparison of the LdMAcP orthologues in Leishmania sp...
May 1, 2015: Biochemical Journal
Juliana Q Reimão, Jordana C Oliveira, Cristiana T Trinconi, Paulo C Cotrim, Adriano C Coelho, Silvia R B Uliana
BACKGROUND: The only oral drug available for the treatment of leishmaniasis is miltefosine, described and approved for visceral leishmaniasis in India. Miltefosine is under evaluation for the treatment of cutaneous leishmaniasis in the Americas although its efficacy for the treatment of human visceral leishmaniasis caused by Leishmania infantum chagasi has not been described. Drug efficacy for visceral leishmaniasis is ideally tested in hamsters, an experimental model that mimics human disease...
February 2015: PLoS Neglected Tropical Diseases
Azam Bolhassani, Martin Muller, Farzin Roohvand, Fatemeh Motevalli, Elnaz Agi, Mehdi Shokri, Mahdieh Motamedi Rad, Sahar Hosseinzadeh
The development of an efficient vaccine against high-risk HPV types can reduce the incidence rates of cervical cancer by generating anti-tumor protective responses. Traditionally, the majority of prophylactic viral vaccines are composed of live, attenuated or inactivated viruses. Among them, the design of an effective and low-cost vaccine is critical. Inactivated vaccines especially heat-killed yeast cells have emerged as a promising approach for generating antigen-specific immunotherapy. Recent studies have indicated that yeast cell wall components possess adjuvant activities...
2014: Human Vaccines & Immunotherapeutics
Tahereh Taheri, Hana Saberi Nik, Negar Seyed, Fatemeh Doustdari, Mohammad-Hossein Etemadzadeh, Fatemeh Torkashvand, Sima Rafati
Because of the lack of an accurate and sensitive tool to evaluate the parasitemia level, treatment or prevention of leishmaniasis remains an important challenge worldwide. To monitor and track leishmanial infection by two parameters in real time, we generated stably transgenic Leishmania that express a bi-reporter protein as fused EGFP and firefly luciferase. Using two reporter genes (egfp-luc) simultaneously increases the experimental sensitivity for detection/diagnosis, and in vitro quantification of parasites as well as real-time infection in mice...
March 2015: Experimental Parasitology
R Lee Reinhardt, Hong-Erh Liang, Katherine Bao, April E Price, Markus Mohrs, Ben L Kelly, Richard M Locksley
Autoinflammatory disease and hyperinflammatory syndromes represent a growing number of diseases associated with inappropriately controlled inflammation in multiple organs. Systemic inflammation commonly results from dysregulated activation of innate immune cells, and therapeutic targeting of the IL-1β pathway has been used to ameliorate some of these diseases. Some hyperinflammatory syndromes, however, such as hemophagocytic lymphohistiocytosis and the newly classified proteasome disability syndromes, are refractory to such treatments, suggesting that other factors or environmental stressors may be contributing...
March 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Laurence U Buxbaum
Chronic cutaneous disease of mice caused by the protozoan parasite Leishmania mexicana requires interleukin-10 (IL-10) and FcγRIII (an activating IgG receptor). Macrophages readily secrete IL-10 in response to IgG-coated amastigotes, making macrophages a prime candidate as the critical source of IL-10. However, indirect evidence suggested that macrophage IL-10 is not essential for chronic disease. I now show directly that mice lacking IL-10 from macrophages and granulocytes still have chronic disease, like wild-type C57BL/6 mice...
April 2015: Infection and Immunity
Samuel Dean, Jack Sunter, Richard J Wheeler, Ian Hodkinson, Eva Gluenz, Keith Gull
One of the first steps in understanding a protein's function is to determine its localization; however, the methods for localizing proteins in some systems have not kept pace with the developments in other fields, creating a bottleneck in the analysis of the large datasets that are generated in the post-genomic era. To address this, we developed tools for tagging proteins in trypanosomatids. We made a plasmid that, when coupled with long primer PCR, can be used to produce transgenes at their endogenous loci encoding proteins tagged at either terminus or within the protein coding sequence...
January 2015: Open Biology
Wen-Wei Zhang, Greg Matlashewski
Leishmania protozoan parasites are the causing agent of leishmaniasis. Depending on the infecting species, Leishmania infection can causes a wide variety of diseases such as self-healing cutaneous lesions by L. major and fatal visceral leishmaniasis by L. donovani and L. infantum. Comparison of the visceral disease causing L. infantum genome with cutaneous disease causing L. major and L. braziliensis genomes has identified 25 L. infantum (L. donovani complex) species-specific genes that are absent or pseudogenes in L...
2015: Methods in Molecular Biology
Steve Oghumu, James C Stock, Sanjay Varikuti, Ran Dong, Cesar Terrazas, Jessica A Edwards, Chad A Rappleye, Ariel Holovatyk, Arlene Sharpe, Abhay R Satoskar
Cutaneous leishmaniasis, caused mainly by Leishmania major, an obligate intracellular parasite, is a disfiguring disease characterized by large skin lesions and is transmitted by a sand fly vector. We previously showed that the chemokine receptor CXCR3 plays a critical role in mediating resistance to cutaneous leishmaniasis caused by Leishmania major. Furthermore, T cells from L. major-susceptible BALB/c but not L. major-resistant C57BL/6 mice fail to efficiently upregulate CXCR3 upon activation. We therefore examined whether transgenic expression of CXCR3 on T cells would enhance resistance to L...
January 2015: Infection and Immunity
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