title: The loss of virulence of histone H1 overexpressing Leishmania donovani parasites is directly associated with a reduction of HSP83 rate of translation.
abstract: Overexpression of Leishmania histone H1 (LeishH1) was previously found to cause a promastigote-to-amastigote differentiation handicap, deregulation of cell-cycle progression, and loss of parasite infectivity. The aim of this study was to identify changes in the proteome of LeishH1 overexpressing parasites associated with the avirulent phenotype observed. 2D-gel electrophoresis analysis revealed only a small protein subset of differentially expressed proteins in the LeishH1 overexpressing promastigotes. Among these was the chaperone HSP83, known for its protective role in Leishmania drug-induced apoptosis, which displayed lower translational rates. To investigate if the lower expression levels of HSP83 are associated with the differentiation handicap, we assayed the thermostability of parasites by subjecting them to heat-shock (25°C→37°C), a natural stress-factor occurring during stage differentiation. Heat-shock promoted apoptosis to a greater extent in the LeishH1 overexpressing parasites. Interestingly, these parasites were not only more sensitive to heat-shock but also to drug-induced [Sb(III)] cell-death. In addition, the restoration of HSP83 levels re-established drug resistance, and restored infectivity to LeishH1 overexpressing parasites in the murine J774 macrophage model. Overall, this study suggests that LeishH1 levels are critical for the parasite's stress-induced adaptation within the mammalian host, and highlights the cross-talk between pathways involved in drug resistance, apoptosis and virulence.
authors: Laboratory of Molecular Parasitology, Department of Microbiology, Hellenic Pasteur Institute, 127 Vas Sofias Ave., Athens, Greece.
authors: Alexandros
authors: A
authors: Alexandratos
authors: Joachim
authors: J
authors: Clos
authors: Martina
authors: M
authors: Samiotaki
authors: Antonia
authors: A
authors: Efstathiou
authors: George
authors: G
authors: Panayotou
authors: Ketty
authors: K
authors: Soteriadou
authors: Despina
authors: D
authors: Smirlis
mesh_terms: D000818:Animals; D002460:Cell Line; D015180:Electrophoresis, Gel, Two-Dimensional; D004705:Endocytosis; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006358:Hot Temperature; D007893:Leishmania donovani / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity* / Q000528:radiation effects; D008264:Macrophages / Q000469:parasitology; D051379:Mice; D014176:Protein Biosynthesis; D020543:Proteome / Q000032:analysis; D015800:Protozoan Proteins / Q000032:analysis / Q000096:biosynthesis*; D013312:Stress, Physiological; D013696:Temperature; D037521:Virulence Factors / Q000096:biosynthesis*
chemical_list: D006360:Heat-Shock Proteins; D006657:Histones; C490310:Hsp83 protein, protozoan; D020543:Proteome; D015800:Protozoan Proteins; D037521:Virulence Factors