Transgenic overexpression of heat shock protein (HSP83) enhances protein kinase A activity, disrupts GP63 surface protease expression and alters promastigote morphology in Leishmania amazonensis.

Leishmania parasites undergo morphological changes during their infectious life cycle, including developmental transitions within the sandfly vector, culminating in metacyclic stages that are pre-adapted for infection. Upon entering vertebrate host phagocytes, Leishmania differentiate into intracellular amastigotes, the form that is ultimately transmitted back to the vector to complete the life cycle. Although environmental conditions that induce these cellular transitions are well-established, molecular mechanisms governing Leishmania morphologic differentiation in response to these cues remain largely uncharacterized.

Dynamic modulation of Leishmania cytochrome c oxidase subunit IV (LmCOX4) expression in response to mammalian temperature.

The Leishmania LACK antigen is a ribosome-associated protein that facilitates expression of mitochondrial cytochrome c oxidase subunit IV (LmCOX4) to support parasite mitochondrial fitness and virulence within the vertebrate host. To further examine the relationship between LACK, its putative ribosome binding motif and LmCOX4, we compared the kinetics of LmCOX4 expression following temperature elevation in wildtype LACK (LACK WT) and LACK-putative ribosome-binding mutant (LACK) L. major.

Disruption of the Putative Ribosome-Binding Motif of a Scaffold Protein Impairs Cytochrome Oxidase Subunit Expression in .

During their parasitic life cycle, through sandflies and vertebrate hosts, parasites confront strikingly different environments, including abrupt changes in pH and temperature, to which they must rapidly adapt. These adaptations include alterations in gene expression, metabolism, and morphology, allowing them to thrive as promastigotes in the sandfly and as intracellular amastigotes in the vertebrate host. A critical aspect of metabolic adaptation to these changes is maintenance of efficient mitochondrial function in the hostile vertebrate environment.

A novel model for IFN-γ-mediated autoinflammatory syndromes.

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.

LACK, a RACK1 ortholog, facilitates cytochrome c oxidase subunit expression to promote Leishmania major fitness.

Leishmania are kinetoplastid parasites that cause the sandfly-transmitted disease leishmaniasis. To maintain fitness throughout their infectious life cycle, Leishmania must undergo rapid metabolic adaptations to the dramatically distinct environments encountered during transition between sandfly and vertebrate hosts. We performed proteomic and immunoblot analyses of attenuated L.

Molecular and cellular characterization of an AT-hook protein from Leishmania.

AT-rich DNA, and the proteins that bind it (AT-hook proteins), modulate chromosome structure and function in most eukaryotes. Unlike other trypanosomatids, the genome of Leishmania species is unusually GC-rich, and the regulation of Leishmania chromosome structure, replication, partitioning is not fully understood. Because AT-hook proteins modulate these functions in other eukaryotes, we examined whether AT-hook proteins are encoded in the Leishmania genome, to test their potential functions.

The oligopeptidase B of Leishmania regulates parasite enolase and immune evasion.

Proteases are a ubiquitous group of enzymes that play key roles in the life cycle of parasites, in the host-parasite relationship, and in the pathogenesis of parasitic diseases. Furthermore, proteases are targets for the development of new anti-parasitic therapy. Protozoan parasites like Leishmania predominantly express Clan CA cysteine proteases for key life cycle functions.

Leishmania subtilisin is a maturase for the trypanothione reductase system and contributes to disease pathology.

Proteases are a ubiquitous group of enzymes that play key roles in the life cycle of parasites, in the host-parasite relationship, and in the pathogenesis of parasitic diseases. Furthermore, proteases are druggable targets for the development of new anti-parasitic therapy. The subtilisin protease (SUB; Clan SB, family S8) of Leishmania donovani was cloned and found to possess a unique catalytic triad.

Suppression of LPS-induced inflammatory responses in macrophages infected with Leishmania.

Background: Chronic inflammation activated by macrophage innate pathogen recognition receptors such as TLR4 can lead to a range of inflammatory diseases, including atherosclerosis, Crohn's disease, arthritis and cancer. Unlike many microbes, the kinetoplastid protozoan pathogen Leishmania has been shown to avoid and even actively suppress host inflammatory cytokine responses, such as LPS-induced IL-12 production. The nature and scope of Leishmania-mediated inflammatory cytokine suppression, however, is not well characterized.

The Leishmania major LACK antigen with an immunodominant epitope at amino acids 156 to 173 is not required for early Th2 development in BALB/c mice.

The Leishmania major LACK antigen contains an immunodominant epitope at amino acids 156 to 173 (LACK(156-173)) that is believed to nucleate the pathological Th2 immune response in susceptible BALB/c mice. To test this hypothesis, we generated L. major parasites that express a mutated LACK that fails to activate Vbeta4/Valpha8 T-cell receptor transgenic T cells specific for this epitope.

Leishmania major LACK antigen is required for efficient vertebrate parasitization.

The Leishmania major LACK antigen is a key target of the immune response in susceptible BALB/c mice and remains a viable vaccine candidate for human leishmaniasis. We describe the genomic organization of the four lack genes in the L. major diploid genome together with results of selected lack gene targeting.