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Leishmania Spp. (leishmania + spp)

Distribution by Scientific Domains

Life Sciences	50%

Selected Abstracts

A novel form of NF-,B is induced by Leishmania infection: Involvement in macrophage gene expression

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2008
David
Abstract Leishmania spp. are obligate intracellular parasites that inhabit the phagolysosomes of macrophages. Manipulation of host cell signaling pathways and gene expression by Leishmania is critical for Leishmania's survival and resultant pathology. Here, we show that infection of macrophages with Leishmania promastigotes in vitro causes specific cleavage of the NF-,B p65RelA subunit. Cleavage occurs in the cytoplasm and is dependent on the Leishmania protease gp63. The resulting fragment, p35RelA, migrates to the nucleus, where it binds DNA as a heterodimer with NF-,B p50. Importantly, induction of chemokine gene expression (MIP-2/CXCL2, MCP-1/CCL2, MIP-1,/CCL3, MIP-1,/CCL4) by Leishmania is NF-,B dependent, which implies that p35RelA/p50 dimers are able to activate transcription, despite the absence of a recognized transcriptional transactivation domain. NF-,B cleavage was observed following infection with a range of pathogenic species, including L.,donovani, L.,major, L.,mexicana, and L.,(Viannia) braziliensis, but not the non-pathogenic L.,tarentolae or treatment with IFN-,. These results indicate a novel mechanism by which a pathogen can subvert a macrophage's regulatory pathways to alter NF-,B activity. [source]

Proteomic examination of Leishmania chagasi plasma membrane proteins: Contrast between avirulent and virulent (metacyclic) parasite forms

PROTEOMICS - CLINICAL APPLICATIONS, Issue 1 2010
Chaoqun Yao
Abstract Purpose: About two million new cases of leishmaniasis with 50 000 associated deaths occur worldwide each year. Promastigotes of the causative Leishmania spp. develop from the procyclic stage to the highly virulent metacyclic stage within the sand fly vector. We hypothesized that proteins important for promastigote virulence might be uniquely represented in the plasma membrane of metacyclic, but not procyclic, promastigotes. Experimental design: Procyclic (logarithmic) promastigotes and purified metacyclic promastigotes from stationary phase cultures of Leishmania chagasi were used to prepare membrane preparations either by surface biotinylation-streptavidin affinity separation or by octyl glucoside detergent extraction. Results: These membrane fractions were enriched over 130- and 250-fold, respectively, as estimated by Western blotting for the plasma membrane's major surface protease. Hundreds or dozens of proteins were identified by LC-MS/MS in the surface biotinylation or detergent extraction, respectively. Confocal microscopy suggested the difference between the lists was due to the fact that proteins localized both on the surface membrane and within the flagellar pocket were accessible to surface biotinylation, whereas only proteins on the membrane were obtained by detergent extraction. Using detergent extraction, we found different proteins were present in membranes of the procyclic stage compared to metacyclic stage promastigotes. Several dozen were stage specific. Conclusions and clinical relevance: These data provide a foundation for identifying virulence factors in the plasma membranes of Leishmania spp. promastigotes during metacyclogenesis. [source]

Differences in human macrophage receptor usage, lysosomal fusion kinetics and survival between logarithmic and metacyclic Leishmania infantum chagasi promastigotes

CELLULAR MICROBIOLOGY, Issue 12 2009
Norikiyo Ueno
Summary The obligate intracellular protozoan, Leishmania infantum chagasi (Lic) undergoes receptor-mediated phagocytosis by macrophages followed by a transient delay in phagolysosome maturation. We found differences in the pathway through which virulent Lic metacyclic promastigotes or avirulent logarithmic promastigotes are phagocytosed by human monocyte-derived macrophages (MDMs). Both logarithmic and metacyclic promastigotes entered MDMs through a compartment lined by the third complement receptor (CR3). In contrast, many logarithmic promastigotes entered through vacuoles lined by mannose receptors (MR) whereas most metacyclic promastigotes did not (P < 0.005). CR3-positive vacuoles containing metacyclic promastigotes stained for caveolin-1 protein, suggesting CR3 localizes in caveolae during phagocytosis. Following entry, the kinetics of phagolysosomal maturation and intracellular survival also differed. Vacuoles containing metacyclic parasites did not accumulate lysosome-associated membrane protein-1 (LAMP-1) at early times after phagocytosis, whereas vacuoles with logarithmic promastigotes did. MDMs phagocytosed greater numbers of logarithmic than metacyclic promastigotes, yet metacyclics ultimately replicated intracellularly with greater efficiency. These data suggest that virulent metacyclic Leishmania promastigotes fail to ligate macrophage MR, and enter through a path that ultimately enhances intracellular survival. The relatively quiescent entry of virulent Leishmania spp. into macrophages may be accounted for by the ability of metacyclic promastigotes to selectively bypass deleterious entry pathways. [source]

Synthesis of Bicyclic N -Arylmethyl-Substituted Iminoribitol Derivatives as Selective Nucleoside Hydrolase Inhibitors

CHEMMEDCHEM, Issue 2 2009
Maya Berg
Abstract A series of bicyclicN -arylmethyl-substituted iminoribitols were synthesised and evaluated in,vitro against T.,vivax nucleoside hydrolase. The importance of the N,Asp40 interaction was confirmed and depends on an optimal pKa value, which can be influenced by substituents. The compounds were active inhibitors of nucleoside hydrolase (IAG-NH) and are inactive against human purine nucleoside phosphorylase. The purine metabolism of Trypanosoma and Leishmania spp. provides a good target in the search for new selective drugs. Bicyclic N -arylmethyl-substituted iminoribitols were developed as inhibitors of T.,vivax nucleoside hydrolase, a key enzyme of the purine salvage pathway. The obtained results and structure,activity data confirmed our model for inhibitor binding with a hydrogen bond between a nitrogen atom of the nucleobase mimetic and the protonated Asp40 from the enzyme. This interaction depends on an optimal pKa value, which can be influenced by the electronic properties of the substituents. These compounds are potent, selective inhibitors of nucleoside hydrolase and are inactive toward human nucleoside phosphorylase. [source]