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Transgenic leishmania

Matheus Batista Carneiro, Leah Shan Hohman, Jackson G Egen, Nathan C Peters
Intra-vital two-photon microscopy (2P-IVM) allows for in-situ investigation of tissue organization, cell behavior and the dynamic interactions between different cell types in their natural environment. This methodology has also expanded our understanding of the immune response against pathogens. Leishmania are protozoan intracellular parasites that have adapted to successfully establish infection within the context of an inflammatory response in the skin following transmission by the bite of an infected sand fly...
April 18, 2017: Methods: a Companion to Methods in Enzymology
Pedro H F Stroppa, Luciana M R Antinarelli, Arturene M L Carmo, Jacy Gameiro, Elaine S Coimbra, Adilson D da Silva
Here, we report the effect of new non-classical bioisosteres of miltefosine on Leishmania amazonensis. Fifteen compounds were synthesized and the compound dhmtAc, containing an acetate anion, a side chain of 10 carbon atoms linked to N-1 and a methyl group linked to N-3, showed high and selective biological activity against L. amazonensis. On the intracellular amastigotes, stages of the parasite related to human disease, the IC50 values were near or similar to the 1.0μM (0.9, 0.8 and 1.0μM on L. amazonensis-WT, and two transgenic L...
March 28, 2017: Bioorganic & Medicinal Chemistry
Andrés Vacas, Conor Sugden, Óscar Velasco-Rodriguez, Miriam Algarabel-Olona, José Peña-Guerrero, Esther Larrea, Celia Fernández-Rubio, Paul A Nguewa
Leishmania is the causative agent of leishmaniasis, a neglected tropical disease that affects more than 12 million people around the world. Current treatments are toxic and poorly effective due to the acquisition of resistance within Leishmania populations. Thus, the pursuit for new antileishmanial drugs is a priority. The available methods for drug screening based on colorimetric assays using vital dyes are time-consuming. Currently, the use of fluorescent reporter proteins is replacing the use of viability indicator dyes...
2017: Journal of Parasitology Research
Neeradi Dinesh, Soumya Neelagiri, Vinay Kumar, Sushma Singh
In the present study, glycyrrhizic acid (GA) the main component of Glycyrrhiza glabra was evaluated for its efficacy as antileishmanial agent and its mode of action explored. GA inhibits promastigotes and intracellular amastigotes in a dose dependent manner at an IC50 value of 34 ± 3.0 μM and 20 ± 4.2 μM respectively. GA was non-toxic against THP-1 macrophage host cell line. GA was found to inhibit recombinant Leishmania donovani HMG-CoA reductase (LdHMGR) enzyme at the half-maximum inhibitory concentration of 24 ± 4...
May 2017: Experimental Parasitology
Isabelle Legastelois, Sophie Buffin, Isabelle Peubez, Charlotte Mignon, Régis Sodoyer, Bettina Werle
The increasing demand for recombinant vaccine antigens or immunotherapeutic molecules calls into question the universality of current protein expression systems. Vaccine production can require relatively low amounts of expressed materials, but represents an extremely diverse category consisting of different target antigens with marked structural differences. In contrast, monoclonal antibodies, by definition share key molecular characteristics and require a production system capable of very large outputs, which drives the quest for highly efficient and cost-effective systems...
April 3, 2017: Human Vaccines & Immunotherapeutics
Amjad Hayat Khan, Hadi Bayat, Masoumeh Rajabibazl, Suriana Sabri, Azam Rahimpour
Glycosylation represents the most widespread posttranslational modifications, found in a broad spectrum of natural and therapeutic recombinant proteins. It highly affects bioactivity, site-specificity, stability, solubility, immunogenicity, and serum half-life of glycoproteins. Numerous expression hosts including yeasts, insect cells, transgenic plants, and mammalian cells have been explored for synthesizing therapeutic glycoproteins. However, glycosylation profile of eukaryotic expression systems differs from human...
January 2017: World Journal of Microbiology & Biotechnology
Neelagiri Soumya, Mitesh N Panara, Kishore Babu Neerupudi, Sushma Singh
Leishmaniasis, a neglected tropical disease is endemic in 98 countries and >350 million people are at risk of getting the infection. The existing chemotherapy of Leishmaniasis is limited due to adverse effects, resistance to existing drugs and increasing cases of HIV-Leishmaniasis co-infection. Hence, there is a need to identify novel metabolic pathways for design of new chemical entities. Acetyl-CoA synthetase (AceCS) is an enzyme of acetate metabolic pathway whose functions are unknown in Leishmania parasite...
February 2017: Parasitology International
Eline Rouault, Hervé Lecoeur, Asma Ben Meriem, Paola Minoprio, Sophie Goyard, Thierry Lang
Characterizing the clinical, immunological and parasitological features associated with visceral leishmaniasis is complex. It involves recording in real time and integrating quantitative multi-parametric data sets from parasite infected host tissues. Although several models have been used, hamsters are considered the bona fide experimental model for Leishmania donovani studies. To study visceral leishmaniasis in hamsters we generated virulent transgenic L. donovani that stably express a reporter luciferase protein...
February 2017: Parasitology International
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...
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
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